Antigen binding proteins that bind PD-L1

ABSTRACT

There is disclosed compositions and methods relating to or derived from anti-PD-L1 antibodies. More specifically, there is disclosed fully human antibodies that bind PD-L1, PD-L1-binding fragments and derivatives of such antibodies, and PD-L1-binding polypeptides comprising such fragments. Further still, there is disclosed nucleic acids encoding such antibodies, antibody fragments and derivatives and polypeptides, cells comprising such polynucleotides, methods of making such antibodies, antibody fragments and derivatives and polypeptides, and methods of using such antibodies, antibody fragments and derivatives and polypeptides, including methods of treating or diagnosing subjects having PD-L1 related disorders or conditions, including various inflammatory disorders and various cancers.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application is a divisional of U.S. patent application Ser.No. 16/111,995, filed Aug. 24, 2018, which is a divisional of U.S.patent application Ser. No. 15/619,389, filed Jun. 9, 2017, now U.S.Pat. No. 10,058,609, which is a divisional of U.S. patent applicationSer. No. 14/864,677, filed Sep. 24, 2015, now abandoned, which is adivisional of U.S. patent application Ser. No. 13/907,685, filed May 31,2013, now U.S. Pat. No. 9,175,082, which claims priority to UnitesStates provisional patent applications 61/654,022 filed 31 May 2012 and61/739,982 filed 20 Dec. 2012. The contents of all of these applicationsare hereby incorporated by reference in their entireties.

The instant application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Aug. 24, 2018, isnamed S103014 1130 US D3.txt and is 268 kilobytes in size.

TECHNICAL FIELD

The present disclosure provides compositions and methods relating to orderived from anti-PD-L1 antibodies. More specifically, the presentdisclosure provides human antibodies that bind PD-L1, PD-L1-bindingfragments and derivatives of such antibodies, and PD-L1-bindingpolypeptides comprising such fragments. Further still, the presentdisclosure provides nucleic acids encoding such antibodies, antibodyfragments and derivatives and polypeptides, cells comprising suchpolynucleotides, methods of making such antibodies, antibody fragmentsand derivatives and polypeptides, and methods of using such antibodies,antibody fragments and derivatives and polypeptides, including methodsof treating or diagnosing subjects having PD-L1 related disorders orconditions, including various inflammatory disorders and variouscancers.

BACKGROUND

Programmed death ligand 1 (PD-L1) is a 40 kDa type 1 transmembraneprotein. PD-L1 (human PD-L1 cDNA is composed of the base sequence shownby EMBL/GenBank Acc. No. NM_001267706 and mouse PD-L1 cDNA is composedof the base sequence shown by NM_021893) that is a ligand of PD-1 isexpressed in so-called antigen-presenting cells such as activatedmonocytes and dendritic cells. These cells present interaction moleculesthat induce a variety of immuno-inductive signals to T lymphocytes, andPD-L1 is one of these molecules that induce the inhibitory signal byligating PD-1. It has been revealed that PD-L1 ligation suppressed theactivation (cellular proliferation and induction of various cytokineproductions) of PD-1 expressing T lymphocytes. PD-L1 expression has beenconfirmed in not only immunocompetent cells but also a certain kind oftumor cell lines (cell lines derived from monocytic leukemia, cell linesderived from mast cells, cell lines derived from hepatic carcinomas,cell lines derived from neuroblasts, and cell lines derived from breastcarcinomas) (Nature Immunology (2001), vol. 2, issue 3, p. 261-267).

Programmed death 1 (PD-1) is a member of the CD28 family of receptors,which includes CD28, CTLA-4, ICOS, PD-L1, and BTLA. The initial memberof the family, CD28, was discovered by functional effect on augmenting Tcell proliferation following the addition of monoclonal antibodies(Hutloff et al. (1999) Nature 397:263-266; Hansen et al. (1980)Immunogenics 10:247-260). Two cell surface glycoprotein ligands for PD-1have been identified, PD-L1 and PDL-2, and have been shown todown-regulate T cell activation and cytokine secretion occur uponbinding to PD-1 (Freeman et al. (2000) J. Exp. Med. 192:1027-34;Latchman et al. (2001) Nat. Immunol. 2:261-8; Carter et al. (2002) Eur.J. Immunol. 32:634-43; Ohigashi et al. (2005) Clin. Cancer Res.11:2947-53). Both PD-L1 (B7-H1) and PD-L2 (B7-DC) are B7 homologs thatbind to PD-1. Expression of PD-L1 on the cell surface has also beenshown to be upregulated through IFN-γ stimulation.

PD-L1 expression has been found in several murine and human cancers,including human lung, ovarian and colon carcinoma and various myelomas(Iwai et al. (2002) Proc. Natl. Acad. Sci. USA 99:12293-7; Ohigashi etal. (2005) Clin. Cancer Res. 11:2947-53). PD-L1 has been suggested toplay a role in tumor immunity by increasing apoptosis ofantigen-specific T-cell clones (Dong et al. (2002) Nat. Med. 8:793-800).It has also been suggested that PD-L1 might be involved in intestinalmucosal inflammation and inhibition of PD-L1 suppresses wasting diseaseassociated with colitis (Kanai et al. (2003) J. Immunol. 171:4156-63).

SUMMARY

The present disclosure provides a fully human antibody of an IgG classthat binds to a PD-L1 epitope with a binding affinity of at least 10⁻⁶M,which has a heavy chain variable domain sequence that is at least 95%identical to the amino acid sequences selected from the group consistingof SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9,SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO.19, SEQ ID NO. 21, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ IDNO. 29, SEQ ID NO. 31, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 37, SEQID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47,SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID NO. 55, SEQ ID NO.57, SEQ ID NO. 59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ IDNO. 67, SEQ ID NO. 69, SEQ ID NO. 71, SEQ ID NO. 73, SEQ ID NO. 75, SEQID NO. 77, SEQ ID NO. 79, SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85,SEQ ID NO. 87, SEQ ID NO. 89, SEQ ID NO. 91, SEQ ID NO. 93, SEQ ID NO.95, SEQ ID NO. 97, SEQ ID NO. 99, SEQ ID NO. 101, SEQ ID NO. 103, SEQ IDNO. 105, SEQ ID NO. 107, SEQ ID NO. 109, SEQ ID NO. 111, SEQ ID NO. 113,SEQ ID NO. 115, SEQ ID NO. 117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ IDNO. 123, SEQ ID NO. 125, SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO. 131,SEQ ID NO. 133, SEQ ID NO. 135, SEQ ID NO. 137, SEQ ID NO. 139, SEQ IDNO. 141, SEQ ID NO. 143, SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO. 149,SEQ ID NO. 151, SEQ ID NO. 153, SEQ ID NO. 155, SEQ ID NO. 157, SEQ IDNO. 159, SEQ ID NO. 161, SEQ ID NO. 163, SEQ ID NO. 165, SEQ ID NO. 167,SEQ ID NO. 169, SEQ ID NO. 171, SEQ ID NO. 173, SEQ ID NO. 175, SEQ IDNO. 177, SEQ ID NO. 179, SEQ ID NO. 181, SEQ ID NO. 183, SEQ ID NO. 185,SEQ ID NO. 187, SEQ ID NO. 189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ IDNO. 195, SEQ ID NO. 197, SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO. 203,SEQ ID NO. 205, SEQ ID NO. 207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ IDNO. 213, SEQ ID NO. 215, SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO. 221,SEQ ID NO. 223, SEQ ID NO. 225, SEQ ID NO. 227, SEQ ID NO. 229, SEQ IDNO. 231, SEQ ID NO. 233, SEQ ID NO. 235, SEQ ID NO. 237, SEQ ID NO. 239,SEQ ID NO. 241, and combinations thereof, and that has a light chainvariable domain sequence that is at least 95% identical to the aminoacid sequences selected from the group consisting of SEQ ID NO. 2, SEQID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQID NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22,SEQ ID NO. 24, SEQ ID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO.32, SEQ ID NO. 34, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ IDNO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQID NO. 52, SEQ ID NO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60,SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, SEQ ID NO.70, SEQ ID NO. 72, SEQ ID NO. 74, SEQ ID NO. 76, SEQ ID NO. 78, SEQ IDNO. 80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQID NO. 90, SEQ ID NO. 92, SEQ ID NO. 94, SEQ ID NO. 96, SEQ ID NO. 98,SEQ ID NO. 100, SEQ ID NO. 102, SEQ ID NO. 104, SEQ ID NO. 106, SEQ IDNO. 108, SEQ ID NO. 110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ ID NO. 116,SEQ ID NO. 118, SEQ ID NO. 120, SEQ ID NO. 122, SEQ ID NO. 124, SEQ IDNO. 126, SEQ ID NO. 128, SEQ ID NO. 130, SEQ ID NO. 132, SEQ ID NO. 134,SEQ ID NO. 136, SEQ ID NO. 138, SEQ ID NO. 140, SEQ ID NO. 142, SEQ IDNO. 144, SEQ ID NO. 146, SEQ ID NO. 148, SEQ ID NO. 150, SEQ ID NO. 152,SEQ ID NO. 154, SEQ ID NO. 156, SEQ ID NO. 158, SEQ ID NO. 160, SEQ IDNO. 162, SEQ ID NO. 164, SEQ ID NO. 166, SEQ ID NO. 168, SEQ ID NO. 170,SEQ ID NO. 172, SEQ ID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ IDNO. 180, SEQ ID NO. 182, SEQ ID NO. 184, SEQ ID NO. 186, SEQ ID NO. 188,SEQ ID NO. 190, SEQ ID NO. 192, SEQ ID NO. 194, SEQ ID NO. 196, SEQ IDNO. 198, SEQ ID NO. 200, SEQ ID NO. 202, SEQ ID NO. 204, SEQ ID NO. 206,SEQ ID NO. 208, SEQ ID NO. 210, SEQ ID NO. 212, SEQ ID NO. 214, SEQ IDNO. 216, SEQ ID NO. 218, SEQ ID NO. 220, SEQ ID NO. 222, SEQ ID NO. 224,SEQ ID NO. 226, SEQ ID NO. 228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ IDNO. 234, SEQ ID NO. 236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO. 242,and combinations thereof. Preferably, the fully human antibody has botha heavy chain and a light chain wherein the antibody has a heavychain/light chain variable domain sequence selected from the groupconsisting of SEQ ID NO. 1/SEQ ID NO. 2 (called E6 herein), SEQ ID NO.3/SEQ ID NO. 4 (called E7 herein), SEQ ID NO. 5/SEQ ID NO. 6 (called E9herein), SEQ ID NO. 7/SEQ ID NO. 8 (called E11 herein), SEQ ID NO. 9/SEQID NO. 10 (called F1 herein), SEQ ID NO. 11/SEQ ID NO. 12 (called F4herein), SEQ ID NO. 13/SEQ ID NO. 14 (called F7 herein), SEQ ID NO.15/SEQ ID NO. 16 (called F8 herein), SEQ ID NO. 17/SEQ ID NO. 18 (calledFlt herein), SEQ ID NO. 19/SEQ ID NO. 20 (called G4 herein), SEQ ID NO.21/SEQ ID NO. 22 (called G9 herein), SEQ ID NO. 23/SEQ ID NO. 24 (calledG11 herein), SEQ ID NO. 25/SEQ ID NO. 26 (called G12 herein), SEQ ID NO.27/SEQ ID NO. 28 (called H1 herein), SEQ ID NO. 29/SEQ ID NO. 30 (calledH3 herein), SEQ ID NO. 31/SEQ ID NO. 32 (called H4 herein), SEQ ID NO.33/SEQ ID NO. 34 (called H5 herein), SEQ ID NO. 35/SEQ ID NO. 36 (calledH6 herein), SEQ ID NO. 37/SEQ ID NO. 38 (called H10 herein), SEQ ID NO.39/SEQ ID NO. 40 (called H12 herein), SEQ ID NO. 41/SEQ ID NO. 42(called PDL-D2 herein), SEQ ID NO. 43/SEQ ID NO. 44 (called PDL-D11herein), SEQ ID NO. 45/SEQ ID NO. 46 (called PDL-H1 herein), SEQ ID NO.47/SEQ ID NO. 48 (called RB4 herein), SEQ ID NO. 49/SEQ ID NO. 50(called RB11 herein), SEQ ID NO. 51/SEQ ID NO. 52 (called RC5 herein),SEQ ID NO. 53/SEQ ID NO. 54 (called RF5 herein), SEQ ID NO. 55/SEQ IDNO. 56 (called RG9 herein), SEQ ID NO. 57/SEQ ID NO. 58 (called RD1herein), SEQ ID NO. 59/SEQ ID NO. 60 (called RF11 herein), SEQ ID NO.61/SEQ ID NO. 62 (called RH11 herein), SEQ ID NO. 63/SEQ ID NO. 64(called RD9 herein), SEQ ID NO. 65/SEQ ID NO. 66 (called RE10 herein),SEQ ID NO. 67/SEQ ID NO. 68 (called RA3 herein), SEQ ID NO. 69/SEQ IDNO. 70 (called RG1 herein), SEQ ID NO. 71/SEQ ID NO. 72 (called RB1herein), SEQ ID NO. 73/SEQ ID NO. 74 (called RG7 herein), SEQ ID NO.75/SEQ ID NO. 76 (called RA6 herein), SEQ ID NO. 77/SEQ ID NO. 78(called RA8 herein), SEQ ID NO. 79/SEQ ID NO. 80 (called RA9 herein),SEQ ID NO. 81/SEQ ID NO. 82 (called RB5 herein), SEQ ID NO. 83/SEQ IDNO. 84 (called RB8 herein), SEQ ID NO. 85/SEQ ID NO. 86 (called RC8herein), SEQ ID NO. 87/SEQ ID NO. 88 (called RC10 herein), SEQ ID NO.89/SEQ ID NO. 90 (called RD2 herein), SEQ ID NO. 91/SEQ ID NO. 92(called RE8 herein), SEQ ID NO. 93/SEQ ID NO. 94 (called RE9 herein),SEQ ID NO. 95/SEQ ID NO. 96 (called RG12 herein), SEQ ID NO. 97/SEQ IDNO. 98 (called RSA1 herein), SEQ ID NO. 99/SEQ ID NO. 100 (called R2A7herein), SEQ ID NO. 101/SEQ ID NO. 102 (called R2B12 herein), SEQ ID NO.103/SEQ ID NO. 104 (called R2C9 herein), SEQ ID NO. 105/SEQ ID NO. 106(called R2D5 herein), SEQ ID NO. 107/SEQ ID NO. 108 (called R2D7herein), SEQ ID NO. 109/SEQ ID NO. 110 (called R2F4 herein), SEQ ID NO.111/SEQ ID NO. 112 (called R2A10 herein), SEQ ID NO. 113/SEQ ID NO. 114(called R2E2 herein), SEQ ID NO. 115/SEQ ID NO. 116 (called R3B8herein), SEQ ID NO. 117/SEQ ID NO. 118 (called R3C3 herein), SEQ ID NO.119/SEQ ID NO. 120 (called R3E9 herein), SEQ ID NO. 121/SEQ ID NO. 122(called R3E10 herein), SEQ ID NO. 123/SEQ ID NO. 124 (called R3F7herein), SEQ ID NO. 125/SEQ ID NO. 126 (called R3F10 herein), SEQ ID NO.127/SEQ ID NO. 128 (called R4B10 herein), SEQ ID NO. 129/SEQ ID NO. 130(called R4H1 herein), SEQ ID NO. 131/SEQ ID NO. 132 (called R4A11herein), SEQ ID NO. 133/SEQ ID NO. 134 (called R3D2 herein), SEQ ID NO.135/SEQ ID NO. 136 (called R5B8 herein), SEQ ID NO. 137/SEQ ID NO. 138(called SH1A1Q herein), SEQ ID NO. 139/SEQ ID NO. 140 (called SH1B7B(K)herein), SEQ ID NO. 141/SEQ ID NO. 142 (called SH1C1 herein), SEQ ID NO.143/SEQ ID NO. 144 (called SH1C8 herein), SEQ ID NO. 145/SEQ ID NO. 146(called SH1E10 herein), SEQ ID NO. 147/SEQ ID NO. 148 (called SH1E2herein), SEQ ID NO. 149/SEQ ID NO. 150 (called SH1A9 herein), SEQ ID NO.151/SEQ ID NO. 152 (called SH1B11 herein), SEQ ID NO. 153/SEQ ID NO. 154(called SH1E4 herein), SEQ ID NO. 155/SEQ ID NO. 156 (called SH1B3herein), SEQ ID NO. 157/SEQ ID NO. 158 (called SH1D1 herein), SEQ ID NO.159/SEQ ID NO. 160 (called SH1D2 herein), SEQ ID NO. 161/SEQ ID NO. 162(called SH1D12 herein), SEQ ID NO. 163/SEQ ID NO. 164 (called SH1E1herein), SEQ ID NO. 165/SEQ ID NO. 166 (called SH1G9 herein), SEQ ID NO.167/SEQ ID NO. 168 (called SH1A11 herein), SEQ ID NO. 169/SEQ ID NO. 170(called SH1C2 herein), SEQ ID NO. 171/SEQ ID NO. 172 (called SH1G8herein), SEQ ID NO. 173/SEQ ID NO. 174 (called SH1H2 herein), SEQ ID NO.175/SEQ ID NO. 176 (called SH1B10 herein), SEQ ID NO. 177/SEQ ID NO. 178(called SH1B7A(L) herein), SEQ ID NO. 179/SEQ ID NO. 180 (called SH1E6herein), SEQ ID NO. 181/SEQ ID NO. 182 (called SH1C11 herein), SEQ IDNO. 183/SEQ ID NO. 184 (called SH1A2 herein), SEQ ID NO. 185/SEQ ID NO.186 (called SH1B1 herein), SEQ ID NO. 187/SEQ ID NO. 188 (called R6B2herein), SEQ ID NO. 189/SEQ ID NO. 190 (called R6B7 herein), SEQ ID NO.191/SEQ ID NO. 192 (called R6B11 herein), SEQ ID NO. 193/SEQ ID NO. 194(called R6D1 herein), SEQ ID NO. 195/SEQ ID NO. 196 (called R6C8herein), SEQ ID NO. 197/SEQ ID NO. 198 (called R9G8 herein), SEQ ID NO.199/SEQ ID NO. 200 (called R7D1 herein), SEQ ID NO. 201/SEQ ID NO. 202(called R7D2 herein), SEQ ID NO. 203/SEQ ID NO. 204 (called R7E7herein), SEQ ID NO. 205/SEQ ID NO. 206 (called R7F2 herein), SEQ ID NO.207/SEQ ID NO. 208 (called R7F7 herein), SEQ ID NO. 209/SEQ ID NO. 210(called R9H2 herein), SEQ ID NO. 211/SEQ ID NO. 212 (called R9H6herein), SEQ ID NO. 213/SEQ ID NO. 214 (called H6B1L herein), SEQ ID NO.215/SEQ ID NO. 216 (called H6A1 herein), SEQ ID NO. 217/SEQ ID NO. 218(called H6B1 herein), SEQ ID NO. 219/SEQ ID NO. 220 (called H6B2herein), SEQ ID NO. 221/SEQ ID NO. 222 (called H19C herein), SEQ ID NO.223/SEQ ID NO. 224 (called H110D herein), SEQ ID NO. 225/SEQ ID NO. 226(called H11F herein), SEQ ID NO. 227/SEQ ID NO. 228 (called H1C1herein), SEQ ID NO. 229/SEQ ID NO. 230 (called GPG1A2 herein), SEQ IDNO. 231/SEQ ID NO. 232 (called GPGG8 herein), SEQ ID NO. 233/SEQ ID NO.234 (called GPGG10 herein), SEQ ID NO. 235/SEQ ID NO. 236 (called GPGH7herein), SEQ ID NO. 237/SEQ ID NO. 238 (called GPGH10 herein), SEQ IDNO. 239/SEQ ID NO. 240 (called GPGH11 herein), SEQ ID NO. 241/SEQ ID NO.242 (called GPGH10P herein), and combinations thereof.

The present disclosure provides a Fab fully human antibody fragment,having a variable domain region from a heavy chain and a variable domainregion from a light chain, wherein the heavy chain variable domainsequence that is at least 95% identical to the amino acid sequencesselected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ IDNO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ IDNO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 23, SEQID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 33,SEQ ID NO. 35, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO.43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ IDNO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ ID NO. 61, SEQID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQ ID NO. 71,SEQ ID NO. 73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO. 79, SEQ ID NO.81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ IDNO. 91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ ID NO. 99, SEQID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID NO. 107, SEQ ID NO.109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115, SEQ ID NO. 117, SEQID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ ID NO. 125, SEQ ID NO.127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO. 133, SEQ ID NO. 135, SEQID NO. 137, SEQ ID NO. 139, SEQ ID NO. 141, SEQ ID NO. 143, SEQ ID NO.145, SEQ ID NO. 147, SEQ ID NO. 149, SEQ ID NO. 151, SEQ ID NO. 153, SEQID NO. 155, SEQ ID NO. 157, SEQ ID NO. 159, SEQ ID NO. 161, SEQ ID NO.163, SEQ ID NO. 165, SEQ ID NO. 167, SEQ ID NO. 169, SEQ ID NO. 171, SEQID NO. 173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO. 179, SEQ ID NO.181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO. 187, SEQ ID NO. 189, SEQID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO. 197, SEQ ID NO.199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO. 205, SEQ ID NO. 207, SEQID NO. 209, SEQ ID NO. 211, SEQ ID NO. 213, SEQ ID NO. 215, SEQ ID NO.217, SEQ ID NO. 219, SEQ ID NO. 221, SEQ ID NO. 223, SEQ ID NO. 225, SEQID NO. 227, SEQ ID NO. 229, SEQ ID NO. 231, SEQ ID NO. 233, SEQ ID NO.235, SEQ ID NO. 237, SEQ ID NO. 239, SEQ ID NO. 241, and combinationsthereof, and that has a light chain variable domain sequence that is atleast 95% identical to the amino acid sequences selected from the groupconsisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8,SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO.18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO. 26, SEQ IDNO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ ID NO. 36, SEQID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46,SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ ID NO. 54, SEQ ID NO.56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ IDNO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID NO. 74, SEQID NO. 76, SEQ ID NO. 78, SEQ ID NO. 80, SEQ ID NO. 82, SEQ ID NO. 84,SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID NO. 92, SEQ ID NO.94, SEQ ID NO. 96, SEQ ID NO. 98, SEQ ID NO. 100, SEQ ID NO. 102, SEQ IDNO. 104, SEQ ID NO. 106, SEQ ID NO. 108, SEQ ID NO. 110, SEQ ID NO. 112,SEQ ID NO. 114, SEQ ID NO. 116, SEQ ID NO. 118, SEQ ID NO. 120, SEQ IDNO. 122, SEQ ID NO. 124, SEQ ID NO. 126, SEQ ID NO. 128, SEQ ID NO. 130,SEQ ID NO. 132, SEQ ID NO. 134, SEQ ID NO. 136, SEQ ID NO. 138, SEQ IDNO. 140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO. 146, SEQ ID NO. 148,SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQ ID NO. 156, SEQ IDNO. 158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO. 164, SEQ ID NO. 166,SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO. 172, SEQ ID NO. 174, SEQ IDNO. 176, SEQ ID NO. 178, SEQ ID NO. 180, SEQ ID NO. 182, SEQ ID NO. 184,SEQ ID NO. 186, SEQ ID NO. 188, SEQ ID NO. 190, SEQ ID NO. 192, SEQ IDNO. 194, SEQ ID NO. 196, SEQ ID NO. 198, SEQ ID NO. 200, SEQ ID NO. 202,SEQ ID NO. 204, SEQ ID NO. 206, SEQ ID NO. 208, SEQ ID NO. 210, SEQ IDNO. 212, SEQ ID NO. 214, SEQ ID NO. 216, SEQ ID NO. 218, SEQ ID NO. 220,SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQ ID NO. 228, SEQ IDNO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO. 236, SEQ ID NO. 238,SEQ ID NO. 240, SEQ ID NO. 242, and combinations thereof. Preferably,the fully human antibody Fab fragment has both a heavy chain variabledomain region and a light chain variable domain region wherein theantibody has a heavy chain/light chain variable domain sequence selectedfrom the group consisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQID NO. 4, SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ IDNO. 9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ IDNO. 14, SEQ ID NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ IDNO. 19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ IDNO. 24, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28, SEQ IDNO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID NO. 33/SEQ IDNO. 34, SEQ ID NO. 35/SEQ ID NO. 36, SEQ ID NO. 37/SEQ ID NO. 38, SEQ IDNO. 39/SEQ ID NO. 40, SEQ ID NO. 41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ IDNO. 44, SEQ ID NO. 45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48, SEQ IDNO. 49/SEQ ID NO. 50, SEQ ID NO. 51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ IDNO. 54, SEQ ID NO. 55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ IDNO. 59/SEQ ID NO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ IDNO. 64, SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID NO. 68, SEQ IDNO. 69/SEQ ID NO. 70, SEQ ID NO. 71/SEQ ID NO. 72, SEQ ID NO. 73/SEQ IDNO. 74, SEQ ID NO. 75/SEQ ID NO. 76, SEQ ID NO. 77/SEQ ID NO. 78, SEQ IDNO. 79/SEQ ID NO. 80, SEQ ID NO. 81/SEQ ID NO. 82, SEQ ID NO. 83/SEQ IDNO. 84, SEQ ID NO. 85/SEQ ID NO. 86, SEQ ID NO. 87/SEQ ID NO. 88, SEQ IDNO. 89/SEQ ID NO. 90, SEQ ID NO. 91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ IDNO. 94, SEQ ID NO. 95/SEQ ID NO. 96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ IDNO. 99/SEQ ID NO. 100, SEQ ID NO. 101/SEQ ID NO. 102, SEQ ID NO. 103/SEQID NO. 104, SEQ ID NO. 105/SEQ ID NO. 106, SEQ ID NO. 107/SEQ ID NO.108, SEQ ID NO. 109/SEQ ID NO. 110, SEQ ID NO. 111/SEQ ID NO. 112, SEQID NO. 113/SEQ ID NO. 114, SEQ ID NO. 115/SEQ ID NO. 116, SEQ ID NO.117/SEQ ID NO. 118, SEQ ID NO. 119/SEQ ID NO. 120, SEQ ID NO. 121/SEQ IDNO. 122, SEQ ID NO. 123/SEQ ID NO. 124, SEQ ID NO. 125/SEQ ID NO. 126,SEQ ID NO. 127/SEQ ID NO. 128, SEQ ID NO. 129/SEQ ID NO. 130, SEQ ID NO.131/SEQ ID NO. 132, SEQ ID NO. 133/SEQ ID NO. 134, SEQ ID NO. 135/SEQ IDNO. 136, SEQ ID NO. 137/SEQ ID NO. 138, SEQ ID NO. 139/SEQ ID NO. 140,SEQ ID NO. 141/SEQ ID NO. 142, SEQ ID NO. 143/SEQ ID NO. 144, SEQ ID NO.145/SEQ ID NO. 146, SEQ ID NO. 147/SEQ ID NO. 148, SEQ ID NO. 149/SEQ IDNO. 150, SEQ ID NO. 151/SEQ ID NO. 152, SEQ ID NO. 153/SEQ ID NO. 154,SEQ ID NO. 155/SEQ ID NO. 156, SEQ ID NO. 157/SEQ ID NO. 158, SEQ ID NO.159/SEQ ID NO. 160, SEQ ID NO. 161/SEQ ID NO. 162, SEQ ID NO. 163/SEQ IDNO. 164, SEQ ID NO. 165/SEQ ID NO. 166, SEQ ID NO. 167/SEQ ID NO. 168,SEQ ID NO. 169/SEQ ID NO. 170, SEQ ID NO. 171/SEQ ID NO. 172, SEQ ID NO.173/SEQ ID NO. 174, SEQ ID NO. 175/SEQ ID NO. 176, SEQ ID NO. 177/SEQ IDNO. 178, SEQ ID NO. 179/SEQ ID NO. 180, SEQ ID NO. 181/SEQ ID NO. 182,SEQ ID NO. 183/SEQ ID NO. 184, SEQ ID NO. 185/SEQ ID NO. 186, SEQ ID NO.187/SEQ ID NO. 188, SEQ ID NO. 189/SEQ ID NO. 190, SEQ ID NO. 191/SEQ IDNO. 192, SEQ ID NO. 193/SEQ ID NO. 194, SEQ ID NO. 195/SEQ ID NO. 196,SEQ ID NO. 197/SEQ ID NO. 198, SEQ ID NO. 199/SEQ ID NO. 200, SEQ ID NO.201/SEQ ID NO. 202, SEQ ID NO. 203/SEQ ID NO. 204, SEQ ID NO. 205/SEQ IDNO. 206, SEQ ID NO. 207/SEQ ID NO. 208, SEQ ID NO. 209/SEQ ID NO. 210,SEQ ID NO. 211/SEQ ID NO. 212, SEQ ID NO. 213/SEQ ID NO. 214, SEQ ID NO.215/SEQ ID NO. 216, SEQ ID NO. 217/SEQ ID NO. 218, SEQ ID NO. 219/SEQ IDNO. 220, SEQ ID NO. 221/SEQ ID NO. 222, SEQ ID NO. 223/SEQ ID NO. 224,SEQ ID NO. 225/SEQ ID NO. 226, SEQ ID NO. 227/SEQ ID NO. 228, SEQ ID NO.229/SEQ ID NO. 230, SEQ ID NO. 231/SEQ ID NO. 232, SEQ ID NO. 233/SEQ IDNO. 234, SEQ ID NO. 235/SEQ ID NO. 236, SEQ ID NO. 237/SEQ ID NO. 238,SEQ ID NO. 239/SEQ ID NO. 240, SEQ ID NO. 241/SEQ ID NO. 242, andcombinations thereof.

The present disclosure provides a single chain human antibody, having avariable domain region from a heavy chain and a variable domain regionfrom a light chain and a peptide linker connection the heavy chain andlight chain variable domain regions, wherein the heavy chain variabledomain sequence that is at least 95% identical to the amino acidsequences selected from the group consisting of SEQ ID NO. 1, SEQ ID NO.3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO.13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ IDNO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQID NO. 33, SEQ ID NO. 35, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41,SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO.51, SEQ ID NO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ IDNO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQID NO. 71, SEQ ID NO. 73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO. 79,SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO.89, SEQ ID NO. 91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ IDNO. 99, SEQ ID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID NO. 107,SEQ ID NO. 109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115, SEQ IDNO. 117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ ID NO. 125,SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO. 133, SEQ IDNO. 135, SEQ ID NO. 137, SEQ ID NO. 139, SEQ ID NO. 141, SEQ ID NO. 143,SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO. 149, SEQ ID NO. 151, SEQ IDNO. 153, SEQ ID NO. 155, SEQ ID NO. 157, SEQ ID NO. 159, SEQ ID NO. 161,SEQ ID NO. 163, SEQ ID NO. 165, SEQ ID NO. 167, SEQ ID NO. 169, SEQ IDNO. 171, SEQ ID NO. 173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO. 179,SEQ ID NO. 181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO. 187, SEQ IDNO. 189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO. 197,SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO. 205, SEQ IDNO. 207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ ID NO. 213, SEQ ID NO. 215,SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO. 221, SEQ ID NO. 223, SEQ IDNO. 225, SEQ ID NO. 227, SEQ ID NO. 229, SEQ ID NO. 231, SEQ ID NO. 233,SEQ ID NO. 235, SEQ ID NO. 237, SEQ ID NO. 239, SEQ ID NO. 241, andcombinations thereof, and that has a light chain variable domainsequence that is at least 95% identical to the amino acid sequencesselected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ IDNO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ IDNO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34,SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO.44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ IDNO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72,SEQ ID NO. 74, SEQ ID NO. 76, SEQ ID NO. 78, SEQ ID NO. 80, SEQ ID NO.82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ IDNO. 92, SEQ ID NO. 94, SEQ ID NO. 96, SEQ ID NO. 98, SEQ ID NO. 100, SEQID NO. 102, SEQ ID NO. 104, SEQ ID NO. 106, SEQ ID NO. 108, SEQ ID NO.110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ ID NO. 116, SEQ ID NO. 118, SEQID NO. 120, SEQ ID NO. 122, SEQ ID NO. 124, SEQ ID NO. 126, SEQ ID NO.128, SEQ ID NO. 130, SEQ ID NO. 132, SEQ ID NO. 134, SEQ ID NO. 136, SEQID NO. 138, SEQ ID NO. 140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO.146, SEQ ID NO. 148, SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQID NO. 156, SEQ ID NO. 158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO.164, SEQ ID NO. 166, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO. 172, SEQID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO. 180, SEQ ID NO.182, SEQ ID NO. 184, SEQ ID NO. 186, SEQ ID NO. 188, SEQ ID NO. 190, SEQID NO. 192, SEQ ID NO. 194, SEQ ID NO. 196, SEQ ID NO. 198, SEQ ID NO.200, SEQ ID NO. 202, SEQ ID NO. 204, SEQ ID NO. 206, SEQ ID NO. 208, SEQID NO. 210, SEQ ID NO. 212, SEQ ID NO. 214, SEQ ID NO. 216, SEQ ID NO.218, SEQ ID NO. 220, SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQID NO. 228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO.236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO. 242, and combinationsthereof. Preferably, the fully human single chain antibody has both aheavy chain variable domain region and a light chain variable domainregion, wherein the single chain fully human antibody has a heavychain/light chain variable domain sequence selected from the groupconsisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ IDNO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ IDNO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO. 19/SEQ IDNO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ ID NO. 24, SEQ IDNO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28, SEQ ID NO. 29/SEQ IDNO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID NO. 33/SEQ ID NO. 34, SEQ IDNO. 35/SEQ ID NO. 36, SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ IDNO. 40, SEQ ID NO. 41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ ID NO. 44, SEQ IDNO. 45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ IDNO. 50, SEQ ID NO. 51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ ID NO. 54, SEQ IDNO. 55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID NO. 59/SEQ IDNO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID NO. 64, SEQ IDNO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID NO. 68, SEQ ID NO. 69/SEQ IDNO. 70, SEQ ID NO. 71/SEQ ID NO. 72, SEQ ID NO. 73/SEQ ID NO. 74, SEQ IDNO. 75/SEQ ID NO. 76, SEQ ID NO. 77/SEQ ID NO. 78, SEQ ID NO. 79/SEQ IDNO. 80, SEQ ID NO. 81/SEQ ID NO. 82, SEQ ID NO. 83/SEQ ID NO. 84, SEQ IDNO. 85/SEQ ID NO. 86, SEQ ID NO. 87/SEQ ID NO. 88, SEQ ID NO. 89/SEQ IDNO. 90, SEQ ID NO. 91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ ID NO. 94, SEQ IDNO. 95/SEQ ID NO. 96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ ID NO. 99/SEQ IDNO. 100, SEQ ID NO. 101/SEQ ID NO. 102, SEQ ID NO. 103/SEQ ID NO. 104,SEQ ID NO. 105/SEQ ID NO. 106, SEQ ID NO. 107/SEQ ID NO. 108, SEQ ID NO.109/SEQ ID NO. 110, SEQ ID NO. 111/SEQ ID NO. 112, SEQ ID NO. 113/SEQ IDNO. 114, SEQ ID NO. 115/SEQ ID NO. 116, SEQ ID NO. 117/SEQ ID NO. 118,SEQ ID NO. 119/SEQ ID NO. 120, SEQ ID NO. 121/SEQ ID NO. 122, SEQ ID NO.123/SEQ ID NO. 124, SEQ ID NO. 125/SEQ ID NO. 126, SEQ ID NO. 127/SEQ IDNO. 128, SEQ ID NO. 129/SEQ ID NO. 130, SEQ ID NO. 131/SEQ ID NO. 132,SEQ ID NO. 133/SEQ ID NO. 134, SEQ ID NO. 135/SEQ ID NO. 136, SEQ ID NO.137/SEQ ID NO. 138, SEQ ID NO. 139/SEQ ID NO. 140, SEQ ID NO. 141/SEQ IDNO. 142, SEQ ID NO. 143/SEQ ID NO. 144, SEQ ID NO. 145/SEQ ID NO. 146,SEQ ID NO. 147/SEQ ID NO. 148, SEQ ID NO. 149/SEQ ID NO. 150, SEQ ID NO.151/SEQ ID NO. 152, SEQ ID NO. 153/SEQ ID NO. 154, SEQ ID NO. 155/SEQ IDNO. 156, SEQ ID NO. 157/SEQ ID NO. 158, SEQ ID NO. 159/SEQ ID NO. 160,SEQ ID NO. 161/SEQ ID NO. 162, SEQ ID NO. 163/SEQ ID NO. 164, SEQ ID NO.165/SEQ ID NO. 166, SEQ ID NO. 167/SEQ ID NO. 168, SEQ ID NO. 169/SEQ IDNO. 170, SEQ ID NO. 171/SEQ ID NO. 172, SEQ ID NO. 173/SEQ ID NO. 174,SEQ ID NO. 175/SEQ ID NO. 176, SEQ ID NO. 177/SEQ ID NO. 178, SEQ ID NO.179/SEQ ID NO. 180, SEQ ID NO. 181/SEQ ID NO. 182, SEQ ID NO. 183/SEQ IDNO. 184, SEQ ID NO. 185/SEQ ID NO. 186, SEQ ID NO. 187/SEQ ID NO. 188,SEQ ID NO. 189/SEQ ID NO. 190, SEQ ID NO. 191/SEQ ID NO. 192, SEQ ID NO.193/SEQ ID NO. 194, SEQ ID NO. 195/SEQ ID NO. 196, SEQ ID NO. 197/SEQ IDNO. 198, SEQ ID NO. 199/SEQ ID NO. 200, SEQ ID NO. 201/SEQ ID NO. 202,SEQ ID NO. 203/SEQ ID NO. 204, SEQ ID NO. 205/SEQ ID NO. 206, SEQ ID NO.207/SEQ ID NO. 208, SEQ ID NO. 209/SEQ ID NO. 210, SEQ ID NO. 211/SEQ IDNO. 212, SEQ ID NO. 213/SEQ ID NO. 214, SEQ ID NO. 215/SEQ ID NO. 216,SEQ ID NO. 217/SEQ ID NO. 218, SEQ ID NO. 219/SEQ ID NO. 220, SEQ ID NO.221/SEQ ID NO. 222, SEQ ID NO. 223/SEQ ID NO. 224, SEQ ID NO. 225/SEQ IDNO. 226, SEQ ID NO. 227/SEQ ID NO. 228, SEQ ID NO. 229/SEQ ID NO. 230,SEQ ID NO. 231/SEQ ID NO. 232, SEQ ID NO. 233/SEQ ID NO. 234, SEQ ID NO.235/SEQ ID NO. 236, SEQ ID NO. 237/SEQ ID NO. 238, SEQ ID NO. 239/SEQ IDNO. 240, SEQ ID NO. 241/SEQ ID NO. 242, and combinations thereof.

The present disclosure further provides a method for treating a broadspectrum of mammalian cancers or a broad-spectrum of inflammatorydiseases and autoimmune diseases, comprising administering an effectiveamount of an anti-PD-L1 polypeptide, wherein the anti-PD-L1 polypeptideis selected from the group consisting of a fully human antibody of anIgG class that binds to a PD-L1 epitope with a binding affinity of atleast 10⁻⁶M, a Fab fully human antibody fragment, having a variabledomain region from a heavy chain and a variable domain region from alight chain, a single chain human antibody, having a variable domainregion from a heavy chain and a variable domain region from a lightchain and a peptide linker connection the heavy chain and light chainvariable domain regions, and combinations thereof;

wherein the fully human antibody has a heavy chain variable domainsequence that is at least 95% identical to the amino acid sequencesselected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ IDNO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ IDNO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 23, SEQID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 33,SEQ ID NO. 35, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO.43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ IDNO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ ID NO. 61, SEQID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQ ID NO. 71,SEQ ID NO. 73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO. 79, SEQ ID NO.81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ IDNO. 91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ ID NO. 99, SEQID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID NO. 107, SEQ ID NO.109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115, SEQ ID NO. 117, SEQID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ ID NO. 125, SEQ ID NO.127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO. 133, SEQ ID NO. 135, SEQID NO. 137, SEQ ID NO. 139, SEQ ID NO. 141, SEQ ID NO. 143, SEQ ID NO.145, SEQ ID NO. 147, SEQ ID NO. 149, SEQ ID NO. 151, SEQ ID NO. 153, SEQID NO. 155, SEQ ID NO. 157, SEQ ID NO. 159, SEQ ID NO. 161, SEQ ID NO.163, SEQ ID NO. 165, SEQ ID NO. 167, SEQ ID NO. 169, SEQ ID NO. 171, SEQID NO. 173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO. 179, SEQ ID NO.181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO. 187, SEQ ID NO. 189, SEQID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO. 197, SEQ ID NO.199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO. 205, SEQ ID NO. 207, SEQID NO. 209, SEQ ID NO. 211, SEQ ID NO. 213, SEQ ID NO. 215, SEQ ID NO.217, SEQ ID NO. 219, SEQ ID NO. 221, SEQ ID NO. 223, SEQ ID NO. 225, SEQID NO. 227, SEQ ID NO. 229, SEQ ID NO. 231, SEQ ID NO. 233, SEQ ID NO.235, SEQ ID NO. 237, SEQ ID NO. 239, SEQ ID NO. 241, and combinationsthereof, and that has a light chain variable domain sequence that is atleast 95% identical to the amino acid sequences selected from the groupconsisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8,SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO.18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO. 26, SEQ IDNO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ ID NO. 36, SEQID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46,SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ ID NO. 54, SEQ ID NO.56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ IDNO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID NO. 74, SEQID NO. 76, SEQ ID NO. 78, SEQ ID NO. 80, SEQ ID NO. 82, SEQ ID NO. 84,SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID NO. 92, SEQ ID NO.94, SEQ ID NO. 96, SEQ ID NO. 98, SEQ ID NO. 100, SEQ ID NO. 102, SEQ IDNO. 104, SEQ ID NO. 106, SEQ ID NO. 108, SEQ ID NO. 110, SEQ ID NO. 112,SEQ ID NO. 114, SEQ ID NO. 116, SEQ ID NO. 118, SEQ ID NO. 120, SEQ IDNO. 122, SEQ ID NO. 124, SEQ ID NO. 126, SEQ ID NO. 128, SEQ ID NO. 130,SEQ ID NO. 132, SEQ ID NO. 134, SEQ ID NO. 136, SEQ ID NO. 138, SEQ IDNO. 140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO. 146, SEQ ID NO. 148,SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQ ID NO. 156, SEQ IDNO. 158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO. 164, SEQ ID NO. 166,SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO. 172, SEQ ID NO. 174, SEQ IDNO. 176, SEQ ID NO. 178, SEQ ID NO. 180, SEQ ID NO. 182, SEQ ID NO. 184,SEQ ID NO. 186, SEQ ID NO. 188, SEQ ID NO. 190, SEQ ID NO. 192, SEQ IDNO. 194, SEQ ID NO. 196, SEQ ID NO. 198, SEQ ID NO. 200, SEQ ID NO. 202,SEQ ID NO. 204, SEQ ID NO. 206, SEQ ID NO. 208, SEQ ID NO. 210, SEQ IDNO. 212, SEQ ID NO. 214, SEQ ID NO. 216, SEQ ID NO. 218, SEQ ID NO. 220,SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQ ID NO. 228, SEQ IDNO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO. 236, SEQ ID NO. 238,SEQ ID NO. 240, SEQ ID NO. 242, and combinations thereof;

wherein the Fab fully human antibody fragment has the heavy chainvariable domain sequence that is at least 95% identical to the aminoacid sequences selected from the group consisting of SEQ ID NO. 1, SEQID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21,SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO.31, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 37, SEQ ID NO. 39, SEQ IDNO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQID NO. 51, SEQ ID NO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59,SEQ ID NO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, SEQ ID NO.69, SEQ ID NO. 71, SEQ ID NO. 73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ IDNO. 79, SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQID NO. 89, SEQ ID NO. 91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97,SEQ ID NO. 99, SEQ ID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ IDNO. 107, SEQ ID NO. 109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115,SEQ ID NO. 117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ IDNO. 125, SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO. 133,SEQ ID NO. 135, SEQ ID NO. 137, SEQ ID NO. 139, SEQ ID NO. 141, SEQ IDNO. 143, SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO. 149, SEQ ID NO. 151,SEQ ID NO. 153, SEQ ID NO. 155, SEQ ID NO. 157, SEQ ID NO. 159, SEQ IDNO. 161, SEQ ID NO. 163, SEQ ID NO. 165, SEQ ID NO. 167, SEQ ID NO. 169,SEQ ID NO. 171, SEQ ID NO. 173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ IDNO. 179, SEQ ID NO. 181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO. 187,SEQ ID NO. 189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ IDNO. 197, SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO. 205,SEQ ID NO. 207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ ID NO. 213, SEQ IDNO. 215, SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO. 221, SEQ ID NO. 223,SEQ ID NO. 225, SEQ ID NO. 227, SEQ ID NO. 229, SEQ ID NO. 231, SEQ IDNO. 233, SEQ ID NO. 235, SEQ ID NO. 237, SEQ ID NO. 239, SEQ ID NO. 241,and combinations thereof, and that has the light chain variable domainsequence that is at least 95% identical to the amino acid sequencesselected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ IDNO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ IDNO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34,SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO.44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ IDNO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72,SEQ ID NO. 74, SEQ ID NO. 76, SEQ ID NO. 78, SEQ ID NO. 80, SEQ ID NO.82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ IDNO. 92, SEQ ID NO. 94, SEQ ID NO. 96, SEQ ID NO. 98, SEQ ID NO. 100, SEQID NO. 102, SEQ ID NO. 104, SEQ ID NO. 106, SEQ ID NO. 108, SEQ ID NO.110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ ID NO. 116, SEQ ID NO. 118, SEQID NO. 120, SEQ ID NO. 122, SEQ ID NO. 124, SEQ ID NO. 126, SEQ ID NO.128, SEQ ID NO. 130, SEQ ID NO. 132, SEQ ID NO. 134, SEQ ID NO. 136, SEQID NO. 138, SEQ ID NO. 140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO.146, SEQ ID NO. 148, SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQID NO. 156, SEQ ID NO. 158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO.164, SEQ ID NO. 166, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO. 172, SEQID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO. 180, SEQ ID NO.182, SEQ ID NO. 184, SEQ ID NO. 186, SEQ ID NO. 188, SEQ ID NO. 190, SEQID NO. 192, SEQ ID NO. 194, SEQ ID NO. 196, SEQ ID NO. 198, SEQ ID NO.200, SEQ ID NO. 202, SEQ ID NO. 204, SEQ ID NO. 206, SEQ ID NO. 208, SEQID NO. 210, SEQ ID NO. 212, SEQ ID NO. 214, SEQ ID NO. 216, SEQ ID NO.218, SEQ ID NO. 220, SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQID NO. 228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO.236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO. 242, and combinationsthereof; and

wherein the single chain human antibody has the heavy chain variabledomain sequence that is at least 95% identical to the amino acidsequences selected from the group consisting of SEQ ID NO. 1, SEQ ID NO.3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO.13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ IDNO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQID NO. 33, SEQ ID NO. 35, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41,SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO.51, SEQ ID NO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ IDNO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQID NO. 71, SEQ ID NO. 73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO. 79,SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO.89, SEQ ID NO. 91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ IDNO. 99, SEQ ID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID NO. 107,SEQ ID NO. 109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115, SEQ IDNO. 117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ ID NO. 125,SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO. 133, SEQ IDNO. 135, SEQ ID NO. 137, SEQ ID NO. 139, SEQ ID NO. 141, SEQ ID NO. 143,SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO. 149, SEQ ID NO. 151, SEQ IDNO. 153, SEQ ID NO. 155, SEQ ID NO. 157, SEQ ID NO. 159, SEQ ID NO. 161,SEQ ID NO. 163, SEQ ID NO. 165, SEQ ID NO. 167, SEQ ID NO. 169, SEQ IDNO. 171, SEQ ID NO. 173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO. 179,SEQ ID NO. 181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO. 187, SEQ IDNO. 189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO. 197,SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO. 205, SEQ IDNO. 207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ ID NO. 213, SEQ ID NO. 215,SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO. 221, SEQ ID NO. 223, SEQ IDNO. 225, SEQ ID NO. 227, SEQ ID NO. 229, SEQ ID NO. 231, SEQ ID NO. 233,SEQ ID NO. 235, SEQ ID NO. 237, SEQ ID NO. 239, SEQ ID NO. 241, andcombinations thereof, and that has the light chain variable domainsequence that is at least 95% identical to the amino acid sequencesselected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ IDNO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ IDNO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34,SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO.44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ IDNO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72,SEQ ID NO. 74, SEQ ID NO. 76, SEQ ID NO. 78, SEQ ID NO. 80, SEQ ID NO.82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ IDNO. 92, SEQ ID NO. 94, SEQ ID NO. 96, SEQ ID NO. 98, SEQ ID NO. 100, SEQID NO. 102, SEQ ID NO. 104, SEQ ID NO. 106, SEQ ID NO. 108, SEQ ID NO.110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ ID NO. 116, SEQ ID NO. 118, SEQID NO. 120, SEQ ID NO. 122, SEQ ID NO. 124, SEQ ID NO. 126, SEQ ID NO.128, SEQ ID NO. 130, SEQ ID NO. 132, SEQ ID NO. 134, SEQ ID NO. 136, SEQID NO. 138, SEQ ID NO. 140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO.146, SEQ ID NO. 148, SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQID NO. 156, SEQ ID NO. 158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO.164, SEQ ID NO. 166, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO. 172, SEQID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO. 180, SEQ ID NO.182, SEQ ID NO. 184, SEQ ID NO. 186, SEQ ID NO. 188, SEQ ID NO. 190, SEQID NO. 192, SEQ ID NO. 194, SEQ ID NO. 196, SEQ ID NO. 198, SEQ ID NO.200, SEQ ID NO. 202, SEQ ID NO. 204, SEQ ID NO. 206, SEQ ID NO. 208, SEQID NO. 210, SEQ ID NO. 212, SEQ ID NO. 214, SEQ ID NO. 216, SEQ ID NO.218, SEQ ID NO. 220, SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQID NO. 228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO.236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO. 242, and combinationsthereof.

Preferably, the fully human antibody has both a heavy chain and a lightchain wherein the antibody has a heavy chain/light chain variable domainsequence selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2(called E6 herein), SEQ ID NO. 3/SEQ ID NO. 4 (called E7 herein), SEQ IDNO. 5/SEQ ID NO. 6 (called E9 herein), SEQ ID NO. 7/SEQ ID NO. 8 (calledE11 herein), SEQ ID NO. 9/SEQ ID NO. 10 (called F1 herein), SEQ ID NO.11/SEQ ID NO. 12 (called F4 herein), SEQ ID NO. 13/SEQ ID NO. 14 (calledF7 herein), SEQ ID NO. 15/SEQ ID NO. 16 (called F8 herein), SEQ ID NO.17/SEQ ID NO. 18 (called F11 herein), SEQ ID NO. 19/SEQ ID NO. 20(called G4 herein), SEQ ID NO. 21/SEQ ID NO. 22 (called G9 herein), SEQID NO. 23/SEQ ID NO. 24 (called G11 herein), SEQ ID NO. 25/SEQ ID NO. 26(called G12 herein), SEQ ID NO. 27/SEQ ID NO. 28 (called H1 herein), SEQID NO. 29/SEQ ID NO. 30 (called H3 herein), SEQ ID NO. 31/SEQ ID NO. 32(called H4 herein), SEQ ID NO. 33/SEQ ID NO. 34 (called H5 herein), SEQID NO. 35/SEQ ID NO. 36 (called H6 herein), SEQ ID NO. 37/SEQ ID NO. 38(called H10 herein), SEQ ID NO. 39/SEQ ID NO. 40 (called H12 herein),SEQ ID NO. 41/SEQ ID NO. 42 (called PDL-D2 herein), SEQ ID NO. 43/SEQ IDNO. 44 (called PDL-D11 herein), SEQ ID NO. 45/SEQ ID NO. 46 (calledPDL-H1 herein), SEQ ID NO. 47/SEQ ID NO. 48 (called RB4 herein), SEQ IDNO. 49/SEQ ID NO. 50 (called RB11 herein), SEQ ID NO. 51/SEQ ID NO. 52(called RC5 herein), SEQ ID NO. 53/SEQ ID NO. 54 (called RF5 herein),SEQ ID NO. 55/SEQ ID NO. 56 (called RG9 herein), SEQ ID NO. 57/SEQ IDNO. 58 (called RD1 herein), SEQ ID NO. 59/SEQ ID NO. 60 (called RF11herein), SEQ ID NO. 61/SEQ ID NO. 62 (called RH11 herein), SEQ ID NO.63/SEQ ID NO. 64 (called RD9 herein), SEQ ID NO. 65/SEQ ID NO. 66(called RE10 herein), SEQ ID NO. 67/SEQ ID NO. 68 (called RA3 herein),SEQ ID NO. 69/SEQ ID NO. 70 (called RG1 herein), SEQ ID NO. 71/SEQ IDNO. 72 (called RB1 herein), SEQ ID NO. 73/SEQ ID NO. 74 (called RG7herein), SEQ ID NO. 75/SEQ ID NO. 76 (called RA6 herein), SEQ ID NO.77/SEQ ID NO. 78 (called RA8 herein), SEQ ID NO. 79/SEQ ID NO. 80(called RA9 herein), SEQ ID NO. 81/SEQ ID NO. 82 (called RB5 herein),SEQ ID NO. 83/SEQ ID NO. 84 (called RB8 herein), SEQ ID NO. 85/SEQ IDNO. 86 (called RC8 herein), SEQ ID NO. 87/SEQ ID NO. 88 (called RC10herein), SEQ ID NO. 89/SEQ ID NO. 90 (called RD2 herein), SEQ ID NO.91/SEQ ID NO. 92 (called RE8 herein), SEQ ID NO. 93/SEQ ID NO. 94(called RE9 herein), SEQ ID NO. 95/SEQ ID NO. 96 (called RG12 herein),SEQ ID NO. 97/SEQ ID NO. 98 (called RSA1 herein), SEQ ID NO. 99/SEQ IDNO. 100 (called R2A7 herein), SEQ ID NO. 101/SEQ ID NO. 102 (calledR2B12 herein), SEQ ID NO. 103/SEQ ID NO. 104 (called R2C9 herein), SEQID NO. 105/SEQ ID NO. 106 (called R2D5 herein), SEQ ID NO. 107/SEQ IDNO. 108 (called R2D7 herein), SEQ ID NO. 109/SEQ ID NO. 110 (called R2F4herein), SEQ ID NO. 111/SEQ ID NO. 112 (called R2A10 herein), SEQ ID NO.113/SEQ ID NO. 114 (called R2E2 herein), SEQ ID NO. 115/SEQ ID NO. 116(called R3B8 herein), SEQ ID NO. 117/SEQ ID NO. 118 (called R3C3herein), SEQ ID NO. 119/SEQ ID NO. 120 (called R3E9 herein), SEQ ID NO.121/SEQ ID NO. 122 (called R3E10 herein), SEQ ID NO. 123/SEQ ID NO. 124(called R3F7 herein), SEQ ID NO. 125/SEQ ID NO. 126 (called R3F10herein), SEQ ID NO. 127/SEQ ID NO. 128 (called R4B10 herein), SEQ ID NO.129/SEQ ID NO. 130 (called R4H1 herein), SEQ ID NO. 131/SEQ ID NO. 132(called R4A11 herein), SEQ ID NO. 133/SEQ ID NO. 134 (called R3D2herein), SEQ ID NO. 135/SEQ ID NO. 136 (called R5B8 herein), SEQ ID NO.137/SEQ ID NO. 138 (called SH1A1Q herein), SEQ ID NO. 139/SEQ ID NO. 140(called SH1B7B(K) herein), SEQ ID NO. 141/SEQ ID NO. 142 (called SH1C1herein), SEQ ID NO. 143/SEQ ID NO. 144 (called SH1C8 herein), SEQ ID NO.145/SEQ ID NO. 146 (called SH1E10 herein), SEQ ID NO. 147/SEQ ID NO. 148(called SH1E2 herein), SEQ ID NO. 149/SEQ ID NO. 150 (called SH1A9herein), SEQ ID NO. 151/SEQ ID NO. 152 (called SH1B11 herein), SEQ IDNO. 153/SEQ ID NO. 154 (called SH1E4 herein), SEQ ID NO. 155/SEQ ID NO.156 (called SH1B3 herein), SEQ ID NO. 157/SEQ ID NO. 158 (called SH1D1herein), SEQ ID NO. 159/SEQ ID NO. 160 (called SH1D2 herein), SEQ ID NO.161/SEQ ID NO. 162 (called SH1D12 herein), SEQ ID NO. 163/SEQ ID NO. 164(called SH1E1 herein), SEQ ID NO. 165/SEQ ID NO. 166 (called SH1G9herein), SEQ ID NO. 167/SEQ ID NO. 168 (called SH1A11 herein), SEQ IDNO. 169/SEQ ID NO. 170 (called SH1C2 herein), SEQ ID NO. 171/SEQ ID NO.172 (called SH1G8 herein), SEQ ID NO. 173/SEQ ID NO. 174 (called SH1H2herein), SEQ ID NO. 175/SEQ ID NO. 176 (called SH1B10 herein), SEQ IDNO. 177/SEQ ID NO. 178 (called SH1B7A(L) herein), SEQ ID NO. 179/SEQ IDNO. 180 (called SH1E6 herein), SEQ ID NO. 181/SEQ ID NO. 182 (calledSH1C11 herein), SEQ ID NO. 183/SEQ ID NO. 184 (called SH1A2 herein), SEQID NO. 185/SEQ ID NO. 186 (called SH1B1 herein), SEQ ID NO. 187/SEQ IDNO. 188 (called R6B2 herein), SEQ ID NO. 189/SEQ ID NO. 190 (called R6B7herein), SEQ ID NO. 191/SEQ ID NO. 192 (called R6B11 herein), SEQ ID NO.193/SEQ ID NO. 194 (called R6D1 herein), SEQ ID NO. 195/SEQ ID NO. 196(called R6C8 herein), SEQ ID NO. 197/SEQ ID NO. 198 (called R9G8herein), SEQ ID NO. 199/SEQ ID NO. 200 (called R7D1 herein), SEQ ID NO.201/SEQ ID NO. 202 (called R7D2 herein), SEQ ID NO. 203/SEQ ID NO. 204(called R7E7 herein), SEQ ID NO. 205/SEQ ID NO. 206 (called R7F2herein), SEQ ID NO. 207/SEQ ID NO. 208 (called R7F7 herein), SEQ ID NO.209/SEQ ID NO. 210 (called R9H2 herein), SEQ ID NO. 211/SEQ ID NO. 212(called R9H6 herein), SEQ ID NO. 213/SEQ ID NO. 214 (called H6B1Lherein), SEQ ID NO. 215/SEQ ID NO. 216 (called H6A1 herein), SEQ ID NO.217/SEQ ID NO. 218 (called H6B1 herein), SEQ ID NO. 219/SEQ ID NO. 220(called H6B2 herein), SEQ ID NO. 221/SEQ ID NO. 222 (called H19Cherein), SEQ ID NO. 223/SEQ ID NO. 224 (called H110D herein), SEQ ID NO.225/SEQ ID NO. 226 (called H11F herein), SEQ ID NO. 227/SEQ ID NO. 228(called H1C1 herein), SEQ ID NO. 229/SEQ ID NO. 230 (called GPG1A2herein), SEQ ID NO. 231/SEQ ID NO. 232 (called GPGG8 herein), SEQ ID NO.233/SEQ ID NO. 234 (called GPGG10 herein), SEQ ID NO. 235/SEQ ID NO. 236(called GPGH7 herein), SEQ ID NO. 237/SEQ ID NO. 238 (called GPGH10herein), SEQ ID NO. 239/SEQ ID NO. 240 (called GPGH11 herein), SEQ IDNO. 241/SEQ ID NO. 242 (called GPGH10P herein), and combinationsthereof. Preferably, the fully human antibody Fab fragment has both aheavy chain variable domain region and a light chain variable domainregion wherein the antibody has a heavy chain/light chain variabledomain sequence selected from the group consisting of SEQ ID NO. 1/SEQID NO. 2 (called E6 herein), SEQ ID NO. 3/SEQ ID NO. 4 (called E7herein), SEQ ID NO. 5/SEQ ID NO. 6 (called E9 herein), SEQ ID NO. 7/SEQID NO. 8 (called E11 herein), SEQ ID NO. 9/SEQ ID NO. 10 (called F1herein), SEQ ID NO. 11/SEQ ID NO. 12 (called F4 herein), SEQ ID NO.13/SEQ ID NO. 14 (called F7 herein), SEQ ID NO. 15/SEQ ID NO. 16 (calledF8 herein), SEQ ID NO. 17/SEQ ID NO. 18 (called F11 herein), SEQ ID NO.19/SEQ ID NO. 20 (called G4 herein), SEQ ID NO. 21/SEQ ID NO. 22 (calledG9 herein), SEQ ID NO. 23/SEQ ID NO. 24 (called G11 herein), SEQ ID NO.25/SEQ ID NO. 26 (called G12 herein), SEQ ID NO. 27/SEQ ID NO. 28(called H1 herein), SEQ ID NO. 29/SEQ ID NO. 30 (called H3 herein), SEQID NO. 31/SEQ ID NO. 32 (called H4 herein), SEQ ID NO. 33/SEQ ID NO. 34(called H5 herein), SEQ ID NO. 35/SEQ ID NO. 36 (called H6 herein), SEQID NO. 37/SEQ ID NO. 38 (called H10 herein), SEQ ID NO. 39/SEQ ID NO. 40(called H12 herein), SEQ ID NO. 41/SEQ ID NO. 42 (called PDL-D2 herein),SEQ ID NO. 43/SEQ ID NO. 44 (called PDL-D11 herein), SEQ ID NO. 45/SEQID NO. 46 (called PDL-H1 herein), SEQ ID NO. 47/SEQ ID NO. 48 (calledRB4 herein), SEQ ID NO. 49/SEQ ID NO. 50 (called RB11 herein), SEQ IDNO. 51/SEQ ID NO. 52 (called RC5 herein), SEQ ID NO. 53/SEQ ID NO. 54(called RF5 herein), SEQ ID NO. 55/SEQ ID NO. 56 (called RG9 herein),SEQ ID NO. 57/SEQ ID NO. 58 (called RD1 herein), SEQ ID NO. 59/SEQ IDNO. 60 (called RF11 herein), SEQ ID NO. 61/SEQ ID NO. 62 (called RH11herein), SEQ ID NO. 63/SEQ ID NO. 64 (called RD9 herein), SEQ ID NO.65/SEQ ID NO. 66 (called RE10 herein), SEQ ID NO. 67/SEQ ID NO. 68(called RA3 herein), SEQ ID NO. 69/SEQ ID NO. 70 (called RG1 herein),SEQ ID NO. 71/SEQ ID NO. 72 (called RB1 herein), SEQ ID NO. 73/SEQ IDNO. 74 (called RG7 herein), SEQ ID NO. 75/SEQ ID NO. 76 (called RA6herein), SEQ ID NO. 77/SEQ ID NO. 78 (called RA8 herein), SEQ ID NO.79/SEQ ID NO. 80 (called RA9 herein), SEQ ID NO. 81/SEQ ID NO. 82(called RB5 herein), SEQ ID NO. 83/SEQ ID NO. 84 (called RB8 herein),SEQ ID NO. 85/SEQ ID NO. 86 (called RC8 herein), SEQ ID NO. 87/SEQ IDNO. 88 (called RC10 herein), SEQ ID NO. 89/SEQ ID NO. 90 (called RD2herein), SEQ ID NO. 91/SEQ ID NO. 92 (called RE8 herein), SEQ ID NO.93/SEQ ID NO. 94 (called RE9 herein), SEQ ID NO. 95/SEQ ID NO. 96(called RG12 herein), SEQ ID NO. 97/SEQ ID NO. 98 (called RSA1 herein),SEQ ID NO. 99/SEQ ID NO. 100 (called R2A7 herein), SEQ ID NO. 101/SEQ IDNO. 102 (called R2B12 herein), SEQ ID NO. 103/SEQ ID NO. 104 (calledR2C9 herein), SEQ ID NO. 105/SEQ ID NO. 106 (called R2D5 herein), SEQ IDNO. 107/SEQ ID NO. 108 (called R2D7 herein), SEQ ID NO. 109/SEQ ID NO.110 (called R2F4 herein), SEQ ID NO. 111/SEQ ID NO. 112 (called R2A10herein), SEQ ID NO. 113/SEQ ID NO. 114 (called R2E2 herein), SEQ ID NO.115/SEQ ID NO. 116 (called R3B8 herein), SEQ ID NO. 117/SEQ ID NO. 118(called R3C3 herein), SEQ ID NO. 119/SEQ ID NO. 120 (called R3E9herein), SEQ ID NO. 121/SEQ ID NO. 122 (called R3E10 herein), SEQ ID NO.123/SEQ ID NO. 124 (called R3F7 herein), SEQ ID NO. 125/SEQ ID NO. 126(called R3F10 herein), SEQ ID NO. 127/SEQ ID NO. 128 (called R4B10herein), SEQ ID NO. 129/SEQ ID NO. 130 (called R4H1 herein), SEQ ID NO.131/SEQ ID NO. 132 (called R4A11 herein), SEQ ID NO. 133/SEQ ID NO. 134(called R3D2 herein), SEQ ID NO. 135/SEQ ID NO. 136 (called R5B8herein), SEQ ID NO. 137/SEQ ID NO. 138 (called SH1A1Q herein), SEQ IDNO. 139/SEQ ID NO. 140 (called SH1B7B(K) herein), SEQ ID NO. 141/SEQ IDNO. 142 (called SH1C1 herein), SEQ ID NO. 143/SEQ ID NO. 144 (calledSH1C8 herein), SEQ ID NO. 145/SEQ ID NO. 146 (called SH1E10 herein), SEQID NO. 147/SEQ ID NO. 148 (called SH1E2 herein), SEQ ID NO. 149/SEQ IDNO. 150 (called SH1A9 herein), SEQ ID NO. 151/SEQ ID NO. 152 (calledSH1B11 herein), SEQ ID NO. 153/SEQ ID NO. 154 (called SH1E4 herein), SEQID NO. 155/SEQ ID NO. 156 (called SH1B3 herein), SEQ ID NO. 157/SEQ IDNO. 158 (called SH1D1 herein), SEQ ID NO. 159/SEQ ID NO. 160 (calledSH1D2 herein), SEQ ID NO. 161/SEQ ID NO. 162 (called SH1D12 herein), SEQID NO. 163/SEQ ID NO. 164 (called SH1E1 herein), SEQ ID NO. 165/SEQ IDNO. 166 (called SH1G9 herein), SEQ ID NO. 167/SEQ ID NO. 168 (calledSH1A11 herein), SEQ ID NO. 169/SEQ ID NO. 170 (called SH1C2 herein), SEQID NO. 171/SEQ ID NO. 172 (called SH1G8 herein), SEQ ID NO. 173/SEQ IDNO. 174 (called SH1H2 herein), SEQ ID NO. 175/SEQ ID NO. 176 (calledSH1B10 herein), SEQ ID NO. 177/SEQ ID NO. 178 (called SH1B7A(L) herein),SEQ ID NO. 179/SEQ ID NO. 180 (called SH1E6 herein), SEQ ID NO. 181/SEQID NO. 182 (called SH1C11 herein), SEQ ID NO. 183/SEQ ID NO. 184 (calledSH1A2 herein), SEQ ID NO. 185/SEQ ID NO. 186 (called SH1B1 herein), SEQID NO. 187/SEQ ID NO. 188 (called R6B2 herein), SEQ ID NO. 189/SEQ IDNO. 190 (called R6B7 herein), SEQ ID NO. 191/SEQ ID NO. 192 (calledR6B11 herein), SEQ ID NO. 193/SEQ ID NO. 194 (called R6D1 herein), SEQID NO. 195/SEQ ID NO. 196 (called R6C8 herein), SEQ ID NO. 197/SEQ IDNO. 198 (called R9G8 herein), SEQ ID NO. 199/SEQ ID NO. 200 (called R7D1herein), SEQ ID NO. 201/SEQ ID NO. 202 (called R7D2 herein), SEQ ID NO.203/SEQ ID NO. 204 (called R7E7 herein), SEQ ID NO. 205/SEQ ID NO. 206(called R7F2 herein), SEQ ID NO. 207/SEQ ID NO. 208 (called R7F7herein), SEQ ID NO. 209/SEQ ID NO. 210 (called R9H2 herein), SEQ ID NO.211/SEQ ID NO. 212 (called R9H6 herein), SEQ ID NO. 213/SEQ ID NO. 214(called H6B1L herein), SEQ ID NO. 215/SEQ ID NO. 216 (called H6A1herein), SEQ ID NO. 217/SEQ ID NO. 218 (called H6B1 herein), SEQ ID NO.219/SEQ ID NO. 220 (called H6B2 herein), SEQ ID NO. 221/SEQ ID NO. 222(called H19C herein), SEQ ID NO. 223/SEQ ID NO. 224 (called H110Dherein), SEQ ID NO. 225/SEQ ID NO. 226 (called H11F herein), SEQ ID NO.227/SEQ ID NO. 228 (called H1C1 herein), SEQ ID NO. 229/SEQ ID NO. 230(called GPG1A2 herein), SEQ ID NO. 231/SEQ ID NO. 232 (called GPGG8herein), SEQ ID NO. 233/SEQ ID NO. 234 (called GPGG10 herein), SEQ IDNO. 235/SEQ ID NO. 236 (called GPGH7 herein), SEQ ID NO. 237/SEQ ID NO.238 (called GPGH10 herein), SEQ ID NO. 239/SEQ ID NO. 240 (called GPGH11herein), SEQ ID NO. 241/SEQ ID NO. 242 (called GPGH10P herein), andcombinations thereof. Preferably, the fully human single chain antibodyhas both a heavy chain variable domain region and a light chain variabledomain region, wherein the single chain fully human antibody has a heavychain/light chain variable domain sequence selected from the groupconsisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ IDNO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ IDNO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO. 19/SEQ IDNO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ ID NO. 24, SEQ IDNO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28, SEQ ID NO. 29/SEQ IDNO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID NO. 33/SEQ ID NO. 34, SEQ IDNO. 35/SEQ ID NO. 36, SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ IDNO. 40, SEQ ID NO. 41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ ID NO. 44, SEQ IDNO. 45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ IDNO. 50, SEQ ID NO. 51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ ID NO. 54, SEQ IDNO. 55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID NO. 59/SEQ IDNO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID NO. 64, SEQ IDNO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID NO. 68, SEQ ID NO. 69/SEQ IDNO. 70, SEQ ID NO. 71/SEQ ID NO. 72, SEQ ID NO. 73/SEQ ID NO. 74, SEQ IDNO. 75/SEQ ID NO. 76, SEQ ID NO. 77/SEQ ID NO. 78, SEQ ID NO. 79/SEQ IDNO. 80, SEQ ID NO. 81/SEQ ID NO. 82, SEQ ID NO. 83/SEQ ID NO. 84, SEQ IDNO. 85/SEQ ID NO. 86, SEQ ID NO. 87/SEQ ID NO. 88, SEQ ID NO. 89/SEQ IDNO. 90, SEQ ID NO. 91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ ID NO. 94, SEQ IDNO. 95/SEQ ID NO. 96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ ID NO. 99/SEQ IDNO. 100, SEQ ID NO. 101/SEQ ID NO. 102, SEQ ID NO. 103/SEQ ID NO. 104,SEQ ID NO. 105/SEQ ID NO. 106, SEQ ID NO. 107/SEQ ID NO. 108, SEQ ID NO.109/SEQ ID NO. 110, SEQ ID NO. 111/SEQ ID NO. 112, SEQ ID NO. 113/SEQ IDNO. 114, SEQ ID NO. 115/SEQ ID NO. 116, SEQ ID NO. 117/SEQ ID NO. 118,SEQ ID NO. 119/SEQ ID NO. 120, SEQ ID NO. 121/SEQ ID NO. 122, SEQ ID NO.123/SEQ ID NO. 124, SEQ ID NO. 125/SEQ ID NO. 126, SEQ ID NO. 127/SEQ IDNO. 128, SEQ ID NO. 129/SEQ ID NO. 130, SEQ ID NO. 131/SEQ ID NO. 132,SEQ ID NO. 133/SEQ ID NO. 134, SEQ ID NO. 135/SEQ ID NO. 136, SEQ ID NO.137/SEQ ID NO. 138, SEQ ID NO. 139/SEQ ID NO. 140, SEQ ID NO. 141/SEQ IDNO. 142, SEQ ID NO. 143/SEQ ID NO. 144, SEQ ID NO. 145/SEQ ID NO. 146,SEQ ID NO. 147/SEQ ID NO. 148, SEQ ID NO. 149/SEQ ID NO. 150, SEQ ID NO.151/SEQ ID NO. 152, SEQ ID NO. 153/SEQ ID NO. 154, SEQ ID NO. 155/SEQ IDNO. 156, SEQ ID NO. 157/SEQ ID NO. 158, SEQ ID NO. 159/SEQ ID NO. 160,SEQ ID NO. 161/SEQ ID NO. 162, SEQ ID NO. 163/SEQ ID NO. 164, SEQ ID NO.165/SEQ ID NO. 166, SEQ ID NO. 167/SEQ ID NO. 168, SEQ ID NO. 169/SEQ IDNO. 170, SEQ ID NO. 171/SEQ ID NO. 172, SEQ ID NO. 173/SEQ ID NO. 174,SEQ ID NO. 175/SEQ ID NO. 176, SEQ ID NO. 177/SEQ ID NO. 178, SEQ ID NO.179/SEQ ID NO. 180, SEQ ID NO. 181/SEQ ID NO. 182, SEQ ID NO. 183/SEQ IDNO. 184, SEQ ID NO. 185/SEQ ID NO. 186, SEQ ID NO. 187/SEQ ID NO. 188,SEQ ID NO. 189/SEQ ID NO. 190, SEQ ID NO. 191/SEQ ID NO. 192, SEQ ID NO.193/SEQ ID NO. 194, SEQ ID NO. 195/SEQ ID NO. 196, SEQ ID NO. 197/SEQ IDNO. 198, SEQ ID NO. 199/SEQ ID NO. 200, SEQ ID NO. 201/SEQ ID NO. 202,SEQ ID NO. 203/SEQ ID NO. 204, SEQ ID NO. 205/SEQ ID NO. 206, SEQ ID NO.207/SEQ ID NO. 208, SEQ ID NO. 209/SEQ ID NO. 210, SEQ ID NO. 211/SEQ IDNO. 212, SEQ ID NO. 213/SEQ ID NO. 214, SEQ ID NO. 215/SEQ ID NO. 216,SEQ ID NO. 217/SEQ ID NO. 218, SEQ ID NO. 219/SEQ ID NO. 220, SEQ ID NO.221/SEQ ID NO. 222, SEQ ID NO. 223/SEQ ID NO. 224, SEQ ID NO. 225/SEQ IDNO. 226, SEQ ID NO. 227/SEQ ID NO. 228, SEQ ID NO. 229/SEQ ID NO. 230,SEQ ID NO. 231/SEQ ID NO. 232, SEQ ID NO. 233/SEQ ID NO. 234, SEQ ID NO.235/SEQ ID NO. 236, SEQ ID NO. 237/SEQ ID NO. 238, SEQ ID NO. 239/SEQ IDNO. 240, SEQ ID NO. 241/SEQ ID NO. 242, and combinations thereof.

Preferably, the broad spectrum of mammalian cancers to be treated isselected from the group consisting of ovarian, colon, breast, lungcancers, myelomas, neuroblastic-derived CNS tumors, monocytic leukemias,B-cell derived leukemias, T-cell derived leukemias, B-cell derivedlymphomas, T-cell derived lymphomas, mast cell derived tumors, andcombinations thereof. Preferably, the autoimmune disease or inflammatorydisease is selected from the group consisting of intestinal mucosalinflammation, wasting disease associated with colitis, multiplesclerosis, systemic lupus erythematosus, viral infections, rheumatoidarthritis, osteoarthritis, psoriasis, Cohn's disease, and inflammatorybowel disease.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows anti-PD-L1 antibodies H6 and H10 binding to human PD-L1expressed on human lymphocytes and the EC₅₀ determination in the 100 pMrange

FIG. 2 shows disclosed anti-PD-L1 antibodies binding to humanlymphocytes by FACSAria analysis.

FIG. 3 shows disclosed anti-PD-L1 antibodies H1, H6 and H10 inhibitlymphocyte proliferation.

FIG. 4 shows disclosed anti-PD-L1 antibody H10 inhibit NK cellproliferation.

FIG. 5 shows disclosed anti-PD-L1 antibodies H6 and H10 enhance cellactivation and that the responsive lymphocyte population is the NK cell.

FIG. 6 shows effect of anti-PD-L1 antibodies H6 and H10 on theprogression of disease in a murine model of multiple sclerosis (MS)

FIG. 7 shows the results of EC50 cell binding flow cytometryexperiments, demonstrating that anti-PD-L1 antibody G12 binds the cellsurface of CHO cells transfected with full length PD-L1 in aconcentration dependent manner.

FIG. 8 shows the results of EC50 cell binding flow cytometryexperiments, demonstrating that anti-PD-L1 antibody G12 binds in aconcentration dependent manner to the cell surface of ES-2 ovariancarcinoma cells induced with IFNγ to increase the level of PD-L1expression on these cells.

FIG. 9 shows IC50 data for the blocking of the interaction betweenrecombinant human PD-1 and human PD-L1 expressed on CHO cells byanti-PD-L1 antibody G12.

FIG. 10 shows a mixed lymphocyte reaction (MLR) to evaluate the effectof the antibodies on lymphocyte activity in lymphocyte effector cells.IL-2 secretion was measured in the presence or absence of the anti-PD-L1human monoclonal antibody. The antibodies used were the disclosed G12antibody as compared to prior disclosed antibodies 10A5 and 12A4(Bristol-Myers/Medarex) that were obtained via in-house production fromprior-disclosed antibody sequences (U.S. Patent Application 2009/0055944the disclosure of which is incorporated by reference herein).

FIG. 11 shows a mixed lymphocyte reaction (MLR) was employed todemonstrate the effect of blocking the PD-L1/PD-1 pathway by the listedanti-PD-L1 antibodies on lymphocyte effector cells. IFN-γ secretion wasmeasured in the presence or absence of the anti-PD-L1 human monoclonalantibody. The antibodies used were the disclosed G12 antibody ascompared to prior disclosed antibody 10A5 (Bristol-Myers/Medarex) thatwas obtained via in-house production from prior-disclosed antibodysequences (see U.S. Patent Application 2009/0055944, the disclosure ofwhich is incorporated by reference herein).

FIG. 12 shows a mixed lymphocyte reaction (MLR) was employed to evaluatethe effect of the antibodies on lymphocyte activity by the anti-PD-L1antibodies on lymphocyte effector cells. T cell activation was measuredin the presence or absence of the anti-PD-L1 human monoclonal antibody.The antibodies used were the disclosed G12 antibody as compared to priordisclosed antibodies 10A5 and 12A4 (Bristol-Myers/Medarex) that wereobtained via in-house production from prior-disclosed antibody sequences(U.S. Patent Application 2009/0055944 the disclosure of which isincorporated by reference herein).

FIG. 13 shows a mixed lymphocyte reaction (MLR) was employed to evaluatethe effect of the antibodies on lymphocyte activity by the anti-PD-L1antibodies on lymphocyte effector cells. T cell activation was measuredin the presence or absence of the anti-PD-L1 human monoclonal antibody.The antibodies used were the disclosed H6B1L, RSA1, RA3, RC5, SH1E2,SH1E4, SH1B11, and SH1C8 as compared to prior disclosed antibodies 10A5(Bristol-Myers-Squibb/Medarex) and YW243.55S70 (Roche/Genentech) thatwere obtained via in-house production from prior-disclosed antibodysequences (U.S. Patent Application 2009/0055944 and U.S. PatentApplication US 2010/0203056; the disclosure of which are incorporated byreference herein).

FIG. 14 shows a mixed lymphocyte reaction (MLR) to evaluate the effectof the antibodies on lymphocyte activity in lymphocyte effector cells.IL-2 secretion was measured in the presence or absence of the anti-PD-L1human monoclonal antibody. The antibodies used were the disclosed H6B1L,RSA1, RA3, RC5, SH1E2, SH1E4, SH1B11, and SH1C8 as compared to priordisclosed antibodies 10A5 (Bristol-Myers-Squibb/Medarex) and YW243.55S70(Roche/Genentech) that were obtained via in-house production fromprior-disclosed antibody sequences (U.S. Patent Application 2009/0055944and U.S. Patent Application US 2010/0203056; the disclosure of which areincorporated by reference herein).

FIG. 15 shows a mixed lymphocyte reaction (MLR) was employed todemonstrate the effect of blocking the PD-L1/PD-1 pathway by the listedanti-PD-L1 antibodies on lymphocyte effector cells. IFN-γ secretion wasmeasured in the presence or absence of the anti-PD-L1 human monoclonalantibody. The antibodies used were the disclosed H6B1L, RSA1, RA3, RC5,SH1E2, SH1E4, SH1B11, and SH1C8 as compared to prior disclosedantibodies 10A5 (Bristol-Myers-Squibb/Medarex) and YW243.55S70(Roche/Genentech) that were obtained via in-house production fromprior-disclosed antibody sequences (U.S. Patent Application 2009/0055944and U.S. Patent Application US 2010/0203056; the disclosure of which areincorporated by reference herein).

DETAILED DESCRIPTION

The present disclosure provides a fully human antibody of an IgG classthat binds to a PD-L1 epitope with a binding affinity of 10⁻⁶M or less,that has a heavy chain variable domain sequence that is at least 95%identical to the amino acid sequences selected from the group consistingof SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9,SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO.19, SEQ ID NO. 21, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ IDNO. 29, SEQ ID NO. 31, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 37, SEQID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47,SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID NO. 55, SEQ ID NO.57, SEQ ID NO. 59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ IDNO. 67, SEQ ID NO. 69, SEQ ID NO. 71, SEQ ID NO. 73, SEQ ID NO. 75, SEQID NO. 77, SEQ ID NO. 79, SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85,SEQ ID NO. 87, SEQ ID NO. 89, SEQ ID NO. 91, SEQ ID NO. 93, SEQ ID NO.95, SEQ ID NO. 97, SEQ ID NO. 99, SEQ ID NO. 101, SEQ ID NO. 103, SEQ IDNO. 105, SEQ ID NO. 107, SEQ ID NO. 109, SEQ ID NO. 111, SEQ ID NO. 113,SEQ ID NO. 115, SEQ ID NO. 117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ IDNO. 123, SEQ ID NO. 125, SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO. 131,SEQ ID NO. 133, SEQ ID NO. 135, SEQ ID NO. 137, SEQ ID NO. 139, SEQ IDNO. 141, SEQ ID NO. 143, SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO. 149,SEQ ID NO. 151, SEQ ID NO. 153, SEQ ID NO. 155, SEQ ID NO. 157, SEQ IDNO. 159, SEQ ID NO. 161, SEQ ID NO. 163, SEQ ID NO. 165, SEQ ID NO. 167,SEQ ID NO. 169, SEQ ID NO. 171, SEQ ID NO. 173, SEQ ID NO. 175, SEQ IDNO. 177, SEQ ID NO. 179, SEQ ID NO. 181, SEQ ID NO. 183, SEQ ID NO. 185,SEQ ID NO. 187, SEQ ID NO. 189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ IDNO. 195, SEQ ID NO. 197, SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO. 203,SEQ ID NO. 205, SEQ ID NO. 207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ IDNO. 213, SEQ ID NO. 215, SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO. 221,SEQ ID NO. 223, SEQ ID NO. 225, SEQ ID NO. 227, SEQ ID NO. 229, SEQ IDNO. 231, SEQ ID NO. 233, SEQ ID NO. 235, SEQ ID NO. 237, SEQ ID NO. 239,SEQ ID NO. 241, and combinations thereof, and that has a light chainvariable domain sequence that is at least 95% identical to the aminoacid sequences selected from the group consisting of SEQ ID NO. 2, SEQID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQID NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22,SEQ ID NO. 24, SEQ ID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO.32, SEQ ID NO. 34, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ IDNO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQID NO. 52, SEQ ID NO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60,SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, SEQ ID NO.70, SEQ ID NO. 72, SEQ ID NO. 74, SEQ ID NO. 76, SEQ ID NO. 78, SEQ IDNO. 80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQID NO. 90, SEQ ID NO. 92, SEQ ID NO. 94, SEQ ID NO. 96, SEQ ID NO. 98,SEQ ID NO. 100, SEQ ID NO. 102, SEQ ID NO. 104, SEQ ID NO. 106, SEQ IDNO. 108, SEQ ID NO. 110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ ID NO. 116,SEQ ID NO. 118, SEQ ID NO. 120, SEQ ID NO. 122, SEQ ID NO. 124, SEQ IDNO. 126, SEQ ID NO. 128, SEQ ID NO. 130, SEQ ID NO. 132, SEQ ID NO. 134,SEQ ID NO. 136, SEQ ID NO. 138, SEQ ID NO. 140, SEQ ID NO. 142, SEQ IDNO. 144, SEQ ID NO. 146, SEQ ID NO. 148, SEQ ID NO. 150, SEQ ID NO. 152,SEQ ID NO. 154, SEQ ID NO. 156, SEQ ID NO. 158, SEQ ID NO. 160, SEQ IDNO. 162, SEQ ID NO. 164, SEQ ID NO. 166, SEQ ID NO. 168, SEQ ID NO. 170,SEQ ID NO. 172, SEQ ID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ IDNO. 180, SEQ ID NO. 182, SEQ ID NO. 184, SEQ ID NO. 186, SEQ ID NO. 188,SEQ ID NO. 190, SEQ ID NO. 192, SEQ ID NO. 194, SEQ ID NO. 196, SEQ IDNO. 198, SEQ ID NO. 200, SEQ ID NO. 202, SEQ ID NO. 204, SEQ ID NO. 206,SEQ ID NO. 208, SEQ ID NO. 210, SEQ ID NO. 212, SEQ ID NO. 214, SEQ IDNO. 216, SEQ ID NO. 218, SEQ ID NO. 220, SEQ ID NO. 222, SEQ ID NO. 224,SEQ ID NO. 226, SEQ ID NO. 228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ IDNO. 234, SEQ ID NO. 236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO. 242,and combinations thereof. Preferably, the fully human antibody has botha heavy chain and a light chain wherein the antibody has a heavychain/light chain variable domain sequence selected from the groupconsisting of SEQ ID NO. 1/SEQ ID NO. 2 (called E6 herein), SEQ ID NO.3/SEQ ID NO. 4 (called E7 herein), SEQ ID NO. 5/SEQ ID NO. 6 (called E9herein), SEQ ID NO. 7/SEQ ID NO. 8 (called E11 herein), SEQ ID NO. 9/SEQID NO. 10 (called F1 herein), SEQ ID NO. 11/SEQ ID NO. 12 (called F4herein), SEQ ID NO. 13/SEQ ID NO. 14 (called F7 herein), SEQ ID NO.15/SEQ ID NO. 16 (called F8 herein), SEQ ID NO. 17/SEQ ID NO. 18 (calledF11 herein), SEQ ID NO. 19/SEQ ID NO. 20 (called G4 herein), SEQ ID NO.21/SEQ ID NO. 22 (called G9 herein), SEQ ID NO. 23/SEQ ID NO. 24 (calledG11 herein), SEQ ID NO. 25/SEQ ID NO. 26 (called G12 herein), SEQ ID NO.27/SEQ ID NO. 28 (called H1 herein), SEQ ID NO. 29/SEQ ID NO. 30 (calledH3 herein), SEQ ID NO. 31/SEQ ID NO. 32 (called H4 herein), SEQ ID NO.33/SEQ ID NO. 34 (called H5 herein), SEQ ID NO. 35/SEQ ID NO. 36 (calledH6 herein), SEQ ID NO. 37/SEQ ID NO. 38 (called H10 herein), SEQ ID NO.39/SEQ ID NO. 40 (called H12 herein), SEQ ID NO. 41/SEQ ID NO. 42(called PDL-D2 herein), SEQ ID NO. 43/SEQ ID NO. 44 (called PDL-D11herein), SEQ ID NO. 45/SEQ ID NO. 46 (called PDL-H1 herein), SEQ ID NO.47/SEQ ID NO. 48 (called RB4 herein), SEQ ID NO. 49/SEQ ID NO. 50(called RB11 herein), SEQ ID NO. 51/SEQ ID NO. 52 (called RC5 herein),SEQ ID NO. 53/SEQ ID NO. 54 (called RF5 herein), SEQ ID NO. 55/SEQ IDNO. 56 (called RG9 herein), SEQ ID NO. 57/SEQ ID NO. 58 (called RD1herein), SEQ ID NO. 59/SEQ ID NO. 60 (called RF11 herein), SEQ ID NO.61/SEQ ID NO. 62 (called RH11 herein), SEQ ID NO. 63/SEQ ID NO. 64(called RD9 herein), SEQ ID NO. 65/SEQ ID NO. 66 (called RE10 herein),SEQ ID NO. 67/SEQ ID NO. 68 (called RA3 herein), SEQ ID NO. 69/SEQ IDNO. 70 (called RG1 herein), SEQ ID NO. 71/SEQ ID NO. 72 (called RB1herein), SEQ ID NO. 73/SEQ ID NO. 74 (called RG7 herein), SEQ ID NO.75/SEQ ID NO. 76 (called RA6 herein), SEQ ID NO. 77/SEQ ID NO. 78(called RA8 herein), SEQ ID NO. 79/SEQ ID NO. 80 (called RA9 herein),SEQ ID NO. 81/SEQ ID NO. 82 (called RB5 herein), SEQ ID NO. 83/SEQ IDNO. 84 (called RB8 herein), SEQ ID NO. 85/SEQ ID NO. 86 (called RC8herein), SEQ ID NO. 87/SEQ ID NO. 88 (called RC10 herein), SEQ ID NO.89/SEQ ID NO. 90 (called RD2 herein), SEQ ID NO. 91/SEQ ID NO. 92(called RE8 herein), SEQ ID NO. 93/SEQ ID NO. 94 (called RE9 herein),SEQ ID NO. 95/SEQ ID NO. 96 (called RG12 herein), SEQ ID NO. 97/SEQ IDNO. 98 (called RSA1 herein), SEQ ID NO. 99/SEQ ID NO. 100 (called R2A7herein), SEQ ID NO. 101/SEQ ID NO. 102 (called R2B12 herein), SEQ ID NO.103/SEQ ID NO. 104 (called R2C9 herein), SEQ ID NO. 105/SEQ ID NO. 106(called R2D5 herein), SEQ ID NO. 107/SEQ ID NO. 108 (called R2D7herein), SEQ ID NO. 109/SEQ ID NO. 110 (called R2F4 herein), SEQ ID NO.111/SEQ ID NO. 112 (called R2A10 herein), SEQ ID NO. 113/SEQ ID NO. 114(called R2E2 herein), SEQ ID NO. 115/SEQ ID NO. 116 (called R3B8herein), SEQ ID NO. 117/SEQ ID NO. 118 (called R3C3 herein), SEQ ID NO.119/SEQ ID NO. 120 (called R3E9 herein), SEQ ID NO. 121/SEQ ID NO. 122(called R3E10 herein), SEQ ID NO. 123/SEQ ID NO. 124 (called R3F7herein), SEQ ID NO. 125/SEQ ID NO. 126 (called R3F10 herein), SEQ ID NO.127/SEQ ID NO. 128 (called R4B10 herein), SEQ ID NO. 129/SEQ ID NO. 130(called R4H1 herein), SEQ ID NO. 131/SEQ ID NO. 132 (called R4A11herein), SEQ ID NO. 133/SEQ ID NO. 134 (called R3D2 herein), SEQ ID NO.135/SEQ ID NO. 136 (called R5B8 herein), SEQ ID NO. 137/SEQ ID NO. 138(called SH1A1Q herein), SEQ ID NO. 139/SEQ ID NO. 140 (called SH1B7B(K)herein), SEQ ID NO. 141/SEQ ID NO. 142 (called SH1C1 herein), SEQ ID NO.143/SEQ ID NO. 144 (called SH1C8 herein), SEQ ID NO. 145/SEQ ID NO. 146(called SH1E10 herein), SEQ ID NO. 147/SEQ ID NO. 148 (called SH1E2herein), SEQ ID NO. 149/SEQ ID NO. 150 (called SH1A9 herein), SEQ ID NO.151/SEQ ID NO. 152 (called SH1B11 herein), SEQ ID NO. 153/SEQ ID NO. 154(called SH1E4 herein), SEQ ID NO. 155/SEQ ID NO. 156 (called SH1B3herein), SEQ ID NO. 157/SEQ ID NO. 158 (called SH1D1 herein), SEQ ID NO.159/SEQ ID NO. 160 (called SH1D2 herein), SEQ ID NO. 161/SEQ ID NO. 162(called SH1D12 herein), SEQ ID NO. 163/SEQ ID NO. 164 (called SH1E1herein), SEQ ID NO. 165/SEQ ID NO. 166 (called SH1G9 herein), SEQ ID NO.167/SEQ ID NO. 168 (called SH1A11 herein), SEQ ID NO. 169/SEQ ID NO. 170(called SH1C2 herein), SEQ ID NO. 171/SEQ ID NO. 172 (called SH1G8herein), SEQ ID NO. 173/SEQ ID NO. 174 (called SH1H2 herein), SEQ ID NO.175/SEQ ID NO. 176 (called SH1B10 herein), SEQ ID NO. 177/SEQ ID NO. 178(called SH1B7A(L) herein), SEQ ID NO. 179/SEQ ID NO. 180 (called SH1E6herein), SEQ ID NO. 181/SEQ ID NO. 182 (called SH1C11 herein), SEQ IDNO. 183/SEQ ID NO. 184 (called SH1A2 herein), SEQ ID NO. 185/SEQ ID NO.186 (called SH1B1 herein), SEQ ID NO. 187/SEQ ID NO. 188 (called R6B2herein), SEQ ID NO. 189/SEQ ID NO. 190 (called R6B7 herein), SEQ ID NO.191/SEQ ID NO. 192 (called R6B11 herein), SEQ ID NO. 193/SEQ ID NO. 194(called R6D1 herein), SEQ ID NO. 195/SEQ ID NO. 196 (called R6C8herein), SEQ ID NO. 197/SEQ ID NO. 198 (called R9G8 herein), SEQ ID NO.199/SEQ ID NO. 200 (called R7D1 herein), SEQ ID NO. 201/SEQ ID NO. 202(called R7D2 herein), SEQ ID NO. 203/SEQ ID NO. 204 (called R7E7herein), SEQ ID NO. 205/SEQ ID NO. 206 (called R7F2 herein), SEQ ID NO.207/SEQ ID NO. 208 (called R7F7 herein), SEQ ID NO. 209/SEQ ID NO. 210(called R9H2 herein), SEQ ID NO. 211/SEQ ID NO. 212 (called R9H6herein), SEQ ID NO. 213/SEQ ID NO. 214 (called H6B1L herein), SEQ ID NO.215/SEQ ID NO. 216 (called H6A1 herein), SEQ ID NO. 217/SEQ ID NO. 218(called H6B1 herein), SEQ ID NO. 219/SEQ ID NO. 220 (called H6B2herein), SEQ ID NO. 221/SEQ ID NO. 222 (called H19C herein), SEQ ID NO.223/SEQ ID NO. 224 (called H110D herein), SEQ ID NO. 225/SEQ ID NO. 226(called H11F herein), SEQ ID NO. 227/SEQ ID NO. 228 (called H1C1herein), SEQ ID NO. 229/SEQ ID NO. 230 (called GPG1A2 herein), SEQ IDNO. 231/SEQ ID NO. 232 (called GPGG8 herein), SEQ ID NO. 233/SEQ ID NO.234 (called GPGG10 herein), SEQ ID NO. 235/SEQ ID NO. 236 (called GPGH7herein), SEQ ID NO. 237/SEQ ID NO. 238 (called GPGH10 herein), SEQ IDNO. 239/SEQ ID NO. 240 (called GPGH11 herein), SEQ ID NO. 241/SEQ ID NO.242 (called GPGH10P herein), and combinations thereof.

The present disclosure provides a Fab fully human antibody fragment,having a variable domain region from a heavy chain and a variable domainregion from a light chain, wherein the heavy chain variable domainsequence that is at least 95% identical to the amino acid sequencesselected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ IDNO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ IDNO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 23, SEQID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 33,SEQ ID NO. 35, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO.43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ IDNO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ ID NO. 61, SEQID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQ ID NO. 71,SEQ ID NO. 73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO. 79, SEQ ID NO.81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ IDNO. 91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ ID NO. 99, SEQID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID NO. 107, SEQ ID NO.109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115, SEQ ID NO. 117, SEQID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ ID NO. 125, SEQ ID NO.127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO. 133, SEQ ID NO. 135, SEQID NO. 137, SEQ ID NO. 139, SEQ ID NO. 141, SEQ ID NO. 143, SEQ ID NO.145, SEQ ID NO. 147, SEQ ID NO. 149, SEQ ID NO. 151, SEQ ID NO. 153, SEQID NO. 155, SEQ ID NO. 157, SEQ ID NO. 159, SEQ ID NO. 161, SEQ ID NO.163, SEQ ID NO. 165, SEQ ID NO. 167, SEQ ID NO. 169, SEQ ID NO. 171, SEQID NO. 173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO. 179, SEQ ID NO.181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO. 187, SEQ ID NO. 189, SEQID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO. 197, SEQ ID NO.199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO. 205, SEQ ID NO. 207, SEQID NO. 209, SEQ ID NO. 211, SEQ ID NO. 213, SEQ ID NO. 215, SEQ ID NO.217, SEQ ID NO. 219, SEQ ID NO. 221, SEQ ID NO. 223, SEQ ID NO. 225, SEQID NO. 227, SEQ ID NO. 229, SEQ ID NO. 231, SEQ ID NO. 233, SEQ ID NO.235, SEQ ID NO. 237, SEQ ID NO. 239, SEQ ID NO. 241, and combinationsthereof, and that has a light chain variable domain sequence that is atleast 95% identical to the amino acid sequences selected from the groupconsisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8,SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO.18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO. 26, SEQ IDNO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ ID NO. 36, SEQID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46,SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ ID NO. 54, SEQ ID NO.56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ IDNO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID NO. 74, SEQID NO. 76, SEQ ID NO. 78, SEQ ID NO. 80, SEQ ID NO. 82, SEQ ID NO. 84,SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID NO. 92, SEQ ID NO.94, SEQ ID NO. 96, SEQ ID NO. 98, SEQ ID NO. 100, SEQ ID NO. 102, SEQ IDNO. 104, SEQ ID NO. 106, SEQ ID NO. 108, SEQ ID NO. 110, SEQ ID NO. 112,SEQ ID NO. 114, SEQ ID NO. 116, SEQ ID NO. 118, SEQ ID NO. 120, SEQ IDNO. 122, SEQ ID NO. 124, SEQ ID NO. 126, SEQ ID NO. 128, SEQ ID NO. 130,SEQ ID NO. 132, SEQ ID NO. 134, SEQ ID NO. 136, SEQ ID NO. 138, SEQ IDNO. 140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO. 146, SEQ ID NO. 148,SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQ ID NO. 156, SEQ IDNO. 158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO. 164, SEQ ID NO. 166,SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO. 172, SEQ ID NO. 174, SEQ IDNO. 176, SEQ ID NO. 178, SEQ ID NO. 180, SEQ ID NO. 182, SEQ ID NO. 184,SEQ ID NO. 186, SEQ ID NO. 188, SEQ ID NO. 190, SEQ ID NO. 192, SEQ IDNO. 194, SEQ ID NO. 196, SEQ ID NO. 198, SEQ ID NO. 200, SEQ ID NO. 202,SEQ ID NO. 204, SEQ ID NO. 206, SEQ ID NO. 208, SEQ ID NO. 210, SEQ IDNO. 212, SEQ ID NO. 214, SEQ ID NO. 216, SEQ ID NO. 218, SEQ ID NO. 220,SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQ ID NO. 228, SEQ IDNO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO. 236, SEQ ID NO. 238,SEQ ID NO. 240, SEQ ID NO. 242, and combinations thereof. Preferably,the fully human antibody Fab fragment has both a heavy chain variabledomain region and a light chain variable domain region wherein theantibody has a heavy chain/light chain variable domain sequence selectedfrom the group consisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQID NO. 4, SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ IDNO. 9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ IDNO. 14, SEQ ID NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ IDNO. 19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ IDNO. 24, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28, SEQ IDNO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID NO. 33/SEQ IDNO. 34, SEQ ID NO. 35/SEQ ID NO. 36, SEQ ID NO. 37/SEQ ID NO. 38, SEQ IDNO. 39/SEQ ID NO. 40, SEQ ID NO. 41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ IDNO. 44, SEQ ID NO. 45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48, SEQ IDNO. 49/SEQ ID NO. 50, SEQ ID NO. 51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ IDNO. 54, SEQ ID NO. 55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ IDNO. 59/SEQ ID NO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ IDNO. 64, SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID NO. 68, SEQ IDNO. 69/SEQ ID NO. 70, SEQ ID NO. 71/SEQ ID NO. 72, SEQ ID NO. 73/SEQ IDNO. 74, SEQ ID NO. 75/SEQ ID NO. 76, SEQ ID NO. 77/SEQ ID NO. 78, SEQ IDNO. 79/SEQ ID NO. 80, SEQ ID NO. 81/SEQ ID NO. 82, SEQ ID NO. 83/SEQ IDNO. 84, SEQ ID NO. 85/SEQ ID NO. 86, SEQ ID NO. 87/SEQ ID NO. 88, SEQ IDNO. 89/SEQ ID NO. 90, SEQ ID NO. 91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ IDNO. 94, SEQ ID NO. 95/SEQ ID NO. 96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ IDNO. 99/SEQ ID NO. 100, SEQ ID NO. 101/SEQ ID NO. 102, SEQ ID NO. 103/SEQID NO. 104, SEQ ID NO. 105/SEQ ID NO. 106, SEQ ID NO. 107/SEQ ID NO.108, SEQ ID NO. 109/SEQ ID NO. 110, SEQ ID NO. 111/SEQ ID NO. 112, SEQID NO. 113/SEQ ID NO. 114, SEQ ID NO. 115/SEQ ID NO. 116, SEQ ID NO.117/SEQ ID NO. 118, SEQ ID NO. 119/SEQ ID NO. 120, SEQ ID NO. 121/SEQ IDNO. 122, SEQ ID NO. 123/SEQ ID NO. 124, SEQ ID NO. 125/SEQ ID NO. 126,SEQ ID NO. 127/SEQ ID NO. 128, SEQ ID NO. 129/SEQ ID NO. 130, SEQ ID NO.131/SEQ ID NO. 132, SEQ ID NO. 133/SEQ ID NO. 134, SEQ ID NO. 135/SEQ IDNO. 136, SEQ ID NO. 137/SEQ ID NO. 138, SEQ ID NO. 139/SEQ ID NO. 140,SEQ ID NO. 141/SEQ ID NO. 142, SEQ ID NO. 143/SEQ ID NO. 144, SEQ ID NO.145/SEQ ID NO. 146, SEQ ID NO. 147/SEQ ID NO. 148, SEQ ID NO. 149/SEQ IDNO. 150, SEQ ID NO. 151/SEQ ID NO. 152, SEQ ID NO. 153/SEQ ID NO. 154,SEQ ID NO. 155/SEQ ID NO. 156, SEQ ID NO. 157/SEQ ID NO. 158, SEQ ID NO.159/SEQ ID NO. 160, SEQ ID NO. 161/SEQ ID NO. 162, SEQ ID NO. 163/SEQ IDNO. 164, SEQ ID NO. 165/SEQ ID NO. 166, SEQ ID NO. 167/SEQ ID NO. 168,SEQ ID NO. 169/SEQ ID NO. 170, SEQ ID NO. 171/SEQ ID NO. 172, SEQ ID NO.173/SEQ ID NO. 174, SEQ ID NO. 175/SEQ ID NO. 176, SEQ ID NO. 177/SEQ IDNO. 178, SEQ ID NO. 179/SEQ ID NO. 180, SEQ ID NO. 181/SEQ ID NO. 182,SEQ ID NO. 183/SEQ ID NO. 184, SEQ ID NO. 185/SEQ ID NO. 186, SEQ ID NO.187/SEQ ID NO. 188, SEQ ID NO. 189/SEQ ID NO. 190, SEQ ID NO. 191/SEQ IDNO. 192, SEQ ID NO. 193/SEQ ID NO. 194, SEQ ID NO. 195/SEQ ID NO. 196,SEQ ID NO. 197/SEQ ID NO. 198, SEQ ID NO. 199/SEQ ID NO. 200, SEQ ID NO.201/SEQ ID NO. 202, SEQ ID NO. 203/SEQ ID NO. 204, SEQ ID NO. 205/SEQ IDNO. 206, SEQ ID NO. 207/SEQ ID NO. 208, SEQ ID NO. 209/SEQ ID NO. 210,SEQ ID NO. 211/SEQ ID NO. 212, SEQ ID NO. 213/SEQ ID NO. 214, SEQ ID NO.215/SEQ ID NO. 216, SEQ ID NO. 217/SEQ ID NO. 218, SEQ ID NO. 219/SEQ IDNO. 220, SEQ ID NO. 221/SEQ ID NO. 222, SEQ ID NO. 223/SEQ ID NO. 224,SEQ ID NO. 225/SEQ ID NO. 226, SEQ ID NO. 227/SEQ ID NO. 228, SEQ ID NO.229/SEQ ID NO. 230, SEQ ID NO. 231/SEQ ID NO. 232, SEQ ID NO. 233/SEQ IDNO. 234, SEQ ID NO. 235/SEQ ID NO. 236, SEQ ID NO. 237/SEQ ID NO. 238,SEQ ID NO. 239/SEQ ID NO. 240, SEQ ID NO. 241/SEQ ID NO. 242, andcombinations thereof.

The present disclosure provides a single chain human antibody, having avariable domain region from a heavy chain and a variable domain regionfrom a light chain and a peptide linker connection the heavy chain andlight chain variable domain regions, wherein the heavy chain variabledomain sequence that is at least 95% identical to the amino acidsequences selected from the group consisting of SEQ ID NO. 1, SEQ ID NO.3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO.13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ IDNO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQID NO. 33, SEQ ID NO. 35, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41,SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO.51, SEQ ID NO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ IDNO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQID NO. 71, SEQ ID NO. 73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO. 79,SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO.89, SEQ ID NO. 91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ IDNO. 99, SEQ ID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID NO. 107,SEQ ID NO. 109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115, SEQ IDNO. 117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ ID NO. 125,SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO. 133, SEQ IDNO. 135, SEQ ID NO. 137, SEQ ID NO. 139, SEQ ID NO. 141, SEQ ID NO. 143,SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO. 149, SEQ ID NO. 151, SEQ IDNO. 153, SEQ ID NO. 155, SEQ ID NO. 157, SEQ ID NO. 159, SEQ ID NO. 161,SEQ ID NO. 163, SEQ ID NO. 165, SEQ ID NO. 167, SEQ ID NO. 169, SEQ IDNO. 171, SEQ ID NO. 173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO. 179,SEQ ID NO. 181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO. 187, SEQ IDNO. 189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO. 197,SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO. 205, SEQ IDNO. 207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ ID NO. 213, SEQ ID NO. 215,SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO. 221, SEQ ID NO. 223, SEQ IDNO. 225, SEQ ID NO. 227, SEQ ID NO. 229, SEQ ID NO. 231, SEQ ID NO. 233,SEQ ID NO. 235, SEQ ID NO. 237, SEQ ID NO. 239, SEQ ID NO. 241, andcombinations thereof, and that has a light chain variable domainsequence that is at least 95% identical to the amino acid sequencesselected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ IDNO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ IDNO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34,SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO.44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ IDNO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72,SEQ ID NO. 74, SEQ ID NO. 76, SEQ ID NO. 78, SEQ ID NO. 80, SEQ ID NO.82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ IDNO. 92, SEQ ID NO. 94, SEQ ID NO. 96, SEQ ID NO. 98, SEQ ID NO. 100, SEQID NO. 102, SEQ ID NO. 104, SEQ ID NO. 106, SEQ ID NO. 108, SEQ ID NO.110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ ID NO. 116, SEQ ID NO. 118, SEQID NO. 120, SEQ ID NO. 122, SEQ ID NO. 124, SEQ ID NO. 126, SEQ ID NO.128, SEQ ID NO. 130, SEQ ID NO. 132, SEQ ID NO. 134, SEQ ID NO. 136, SEQID NO. 138, SEQ ID NO. 140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO.146, SEQ ID NO. 148, SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQID NO. 156, SEQ ID NO. 158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO.164, SEQ ID NO. 166, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO. 172, SEQID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO. 180, SEQ ID NO.182, SEQ ID NO. 184, SEQ ID NO. 186, SEQ ID NO. 188, SEQ ID NO. 190, SEQID NO. 192, SEQ ID NO. 194, SEQ ID NO. 196, SEQ ID NO. 198, SEQ ID NO.200, SEQ ID NO. 202, SEQ ID NO. 204, SEQ ID NO. 206, SEQ ID NO. 208, SEQID NO. 210, SEQ ID NO. 212, SEQ ID NO. 214, SEQ ID NO. 216, SEQ ID NO.218, SEQ ID NO. 220, SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQID NO. 228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO.236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO. 242, and combinationsthereof. Preferably, the fully human single chain antibody has both aheavy chain variable domain region and a light chain variable domainregion, wherein the single chain fully human antibody has a heavychain/light chain variable domain sequence selected from the groupconsisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ IDNO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ IDNO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO. 19/SEQ IDNO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ ID NO. 24, SEQ IDNO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28, SEQ ID NO. 29/SEQ IDNO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID NO. 33/SEQ ID NO. 34, SEQ IDNO. 35/SEQ ID NO. 36, SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ IDNO. 40, SEQ ID NO. 41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ ID NO. 44, SEQ IDNO. 45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ IDNO. 50, SEQ ID NO. 51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ ID NO. 54, SEQ IDNO. 55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID NO. 59/SEQ IDNO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID NO. 64, SEQ IDNO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID NO. 68, SEQ ID NO. 69/SEQ IDNO. 70, SEQ ID NO. 71/SEQ ID NO. 72, SEQ ID NO. 73/SEQ ID NO. 74, SEQ IDNO. 75/SEQ ID NO. 76, SEQ ID NO. 77/SEQ ID NO. 78, SEQ ID NO. 79/SEQ IDNO. 80, SEQ ID NO. 81/SEQ ID NO. 82, SEQ ID NO. 83/SEQ ID NO. 84, SEQ IDNO. 85/SEQ ID NO. 86, SEQ ID NO. 87/SEQ ID NO. 88, SEQ ID NO. 89/SEQ IDNO. 90, SEQ ID NO. 91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ ID NO. 94, SEQ IDNO. 95/SEQ ID NO. 96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ ID NO. 99/SEQ IDNO. 100, SEQ ID NO. 101/SEQ ID NO. 102, SEQ ID NO. 103/SEQ ID NO. 104,SEQ ID NO. 105/SEQ ID NO. 106, SEQ ID NO. 107/SEQ ID NO. 108, SEQ ID NO.109/SEQ ID NO. 110, SEQ ID NO. 111/SEQ ID NO. 112, SEQ ID NO. 113/SEQ IDNO. 114, SEQ ID NO. 115/SEQ ID NO. 116, SEQ ID NO. 117/SEQ ID NO. 118,SEQ ID NO. 119/SEQ ID NO. 120, SEQ ID NO. 121/SEQ ID NO. 122, SEQ ID NO.123/SEQ ID NO. 124, SEQ ID NO. 125/SEQ ID NO. 126, SEQ ID NO. 127/SEQ IDNO. 128, SEQ ID NO. 129/SEQ ID NO. 130, SEQ ID NO. 131/SEQ ID NO. 132,SEQ ID NO. 133/SEQ ID NO. 134, SEQ ID NO. 135/SEQ ID NO. 136, SEQ ID NO.137/SEQ ID NO. 138, SEQ ID NO. 139/SEQ ID NO. 140, SEQ ID NO. 141/SEQ IDNO. 142, SEQ ID NO. 143/SEQ ID NO. 144, SEQ ID NO. 145/SEQ ID NO. 146,SEQ ID NO. 147/SEQ ID NO. 148, SEQ ID NO. 149/SEQ ID NO. 150, SEQ ID NO.151/SEQ ID NO. 152, SEQ ID NO. 153/SEQ ID NO. 154, SEQ ID NO. 155/SEQ IDNO. 156, SEQ ID NO. 157/SEQ ID NO. 158, SEQ ID NO. 159/SEQ ID NO. 160,SEQ ID NO. 161/SEQ ID NO. 162, SEQ ID NO. 163/SEQ ID NO. 164, SEQ ID NO.165/SEQ ID NO. 166, SEQ ID NO. 167/SEQ ID NO. 168, SEQ ID NO. 169/SEQ IDNO. 170, SEQ ID NO. 171/SEQ ID NO. 172, SEQ ID NO. 173/SEQ ID NO. 174,SEQ ID NO. 175/SEQ ID NO. 176, SEQ ID NO. 177/SEQ ID NO. 178, SEQ ID NO.179/SEQ ID NO. 180, SEQ ID NO. 181/SEQ ID NO. 182, SEQ ID NO. 183/SEQ IDNO. 184, SEQ ID NO. 185/SEQ ID NO. 186, SEQ ID NO. 187/SEQ ID NO. 188,SEQ ID NO. 189/SEQ ID NO. 190, SEQ ID NO. 191/SEQ ID NO. 192, SEQ ID NO.193/SEQ ID NO. 194, SEQ ID NO. 195/SEQ ID NO. 196, SEQ ID NO. 197/SEQ IDNO. 198, SEQ ID NO. 199/SEQ ID NO. 200, SEQ ID NO. 201/SEQ ID NO. 202,SEQ ID NO. 203/SEQ ID NO. 204, SEQ ID NO. 205/SEQ ID NO. 206, SEQ ID NO.207/SEQ ID NO. 208, SEQ ID NO. 209/SEQ ID NO. 210, SEQ ID NO. 211/SEQ IDNO. 212, SEQ ID NO. 213/SEQ ID NO. 214, SEQ ID NO. 215/SEQ ID NO. 216,SEQ ID NO. 217/SEQ ID NO. 218, SEQ ID NO. 219/SEQ ID NO. 220, SEQ ID NO.221/SEQ ID NO. 222, SEQ ID NO. 223/SEQ ID NO. 224, SEQ ID NO. 225/SEQ IDNO. 226, SEQ ID NO. 227/SEQ ID NO. 228, SEQ ID NO. 229/SEQ ID NO. 230,SEQ ID NO. 231/SEQ ID NO. 232, SEQ ID NO. 233/SEQ ID NO. 234, SEQ ID NO.235/SEQ ID NO. 236, SEQ ID NO. 237/SEQ ID NO. 238, SEQ ID NO. 239/SEQ IDNO. 240, SEQ ID NO. 241/SEQ ID NO. 242, and combinations thereof.

The present disclosure further provides a method for treating a broadspectrum of mammalian cancers or inflammatory diseases or autoimmunediseases, comprising administering an effective amount of an anti-PD-L1polypeptide, wherein the anti-PD-L1 polypeptide is selected from thegroup consisting of a fully human antibody of an IgG class that binds toa PD-L1 epitope with a binding affinity of at least 10⁻⁶M, a Fab fullyhuman antibody fragment, having a variable domain region from a heavychain and a variable domain region from a light chain, a single chainhuman antibody, having a variable domain region from a heavy chain and avariable domain region from a light chain and a peptide linkerconnection the heavy chain and light chain variable domain regions, andcombinations thereof;

wherein the fully human antibody has a heavy chain variable domainsequence that is at least 95% identical to the amino acid sequencesselected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ IDNO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ IDNO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 23, SEQID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 33,SEQ ID NO. 35, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO.43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ IDNO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ ID NO. 61, SEQID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQ ID NO. 71,SEQ ID NO. 73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO. 79, SEQ ID NO.81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ IDNO. 91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ ID NO. 99, SEQID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID NO. 107, SEQ ID NO.109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115, SEQ ID NO. 117, SEQID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ ID NO. 125, SEQ ID NO.127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO. 133, SEQ ID NO. 135, SEQID NO. 137, SEQ ID NO. 139, SEQ ID NO. 141, SEQ ID NO. 143, SEQ ID NO.145, SEQ ID NO. 147, SEQ ID NO. 149, SEQ ID NO. 151, SEQ ID NO. 153, SEQID NO. 155, SEQ ID NO. 157, SEQ ID NO. 159, SEQ ID NO. 161, SEQ ID NO.163, SEQ ID NO. 165, SEQ ID NO. 167, SEQ ID NO. 169, SEQ ID NO. 171, SEQID NO. 173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO. 179, SEQ ID NO.181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO. 187, SEQ ID NO. 189, SEQID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO. 197, SEQ ID NO.199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO. 205, SEQ ID NO. 207, SEQID NO. 209, SEQ ID NO. 211, SEQ ID NO. 213, SEQ ID NO. 215, SEQ ID NO.217, SEQ ID NO. 219, SEQ ID NO. 221, SEQ ID NO. 223, SEQ ID NO. 225, SEQID NO. 227, SEQ ID NO. 229, SEQ ID NO. 231, SEQ ID NO. 233, SEQ ID NO.235, SEQ ID NO. 237, SEQ ID NO. 239, SEQ ID NO. 241, and combinationsthereof, and that has a light chain variable domain sequence that is atleast 95% identical to the amino acid sequences selected from the groupconsisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8,SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO.18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO. 26, SEQ IDNO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ ID NO. 36, SEQID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46,SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ ID NO. 54, SEQ ID NO.56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ IDNO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID NO. 74, SEQID NO. 76, SEQ ID NO. 78, SEQ ID NO. 80, SEQ ID NO. 82, SEQ ID NO. 84,SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID NO. 92, SEQ ID NO.94, SEQ ID NO. 96, SEQ ID NO. 98, SEQ ID NO. 100, SEQ ID NO. 102, SEQ IDNO. 104, SEQ ID NO. 106, SEQ ID NO. 108, SEQ ID NO. 110, SEQ ID NO. 112,SEQ ID NO. 114, SEQ ID NO. 116, SEQ ID NO. 118, SEQ ID NO. 120, SEQ IDNO. 122, SEQ ID NO. 124, SEQ ID NO. 126, SEQ ID NO. 128, SEQ ID NO. 130,SEQ ID NO. 132, SEQ ID NO. 134, SEQ ID NO. 136, SEQ ID NO. 138, SEQ IDNO. 140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO. 146, SEQ ID NO. 148,SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQ ID NO. 156, SEQ IDNO. 158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO. 164, SEQ ID NO. 166,SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO. 172, SEQ ID NO. 174, SEQ IDNO. 176, SEQ ID NO. 178, SEQ ID NO. 180, SEQ ID NO. 182, SEQ ID NO. 184,SEQ ID NO. 186, SEQ ID NO. 188, SEQ ID NO. 190, SEQ ID NO. 192, SEQ IDNO. 194, SEQ ID NO. 196, SEQ ID NO. 198, SEQ ID NO. 200, SEQ ID NO. 202,SEQ ID NO. 204, SEQ ID NO. 206, SEQ ID NO. 208, SEQ ID NO. 210, SEQ IDNO. 212, SEQ ID NO. 214, SEQ ID NO. 216, SEQ ID NO. 218, SEQ ID NO. 220,SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQ ID NO. 228, SEQ IDNO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO. 236, SEQ ID NO. 238,SEQ ID NO. 240, SEQ ID NO. 242, and combinations thereof;

wherein the Fab fully human antibody fragment has the heavy chainvariable domain sequence that is at least 95% identical to the aminoacid sequences selected from the group consisting of SEQ ID NO. 1, SEQID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21,SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO.31, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 37, SEQ ID NO. 39, SEQ IDNO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQID NO. 51, SEQ ID NO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59,SEQ ID NO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, SEQ ID NO.69, SEQ ID NO. 71, SEQ ID NO. 73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ IDNO. 79, SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQID NO. 89, SEQ ID NO. 91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97,SEQ ID NO. 99, SEQ ID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ IDNO. 107, SEQ ID NO. 109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115,SEQ ID NO. 117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ IDNO. 125, SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO. 133,SEQ ID NO. 135, SEQ ID NO. 137, SEQ ID NO. 139, SEQ ID NO. 141, SEQ IDNO. 143, SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO. 149, SEQ ID NO. 151,SEQ ID NO. 153, SEQ ID NO. 155, SEQ ID NO. 157, SEQ ID NO. 159, SEQ IDNO. 161, SEQ ID NO. 163, SEQ ID NO. 165, SEQ ID NO. 167, SEQ ID NO. 169,SEQ ID NO. 171, SEQ ID NO. 173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ IDNO. 179, SEQ ID NO. 181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO. 187,SEQ ID NO. 189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ IDNO. 197, SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO. 205,SEQ ID NO. 207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ ID NO. 213, SEQ IDNO. 215, SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO. 221, SEQ ID NO. 223,SEQ ID NO. 225, SEQ ID NO. 227, SEQ ID NO. 229, SEQ ID NO. 231, SEQ IDNO. 233, SEQ ID NO. 235, SEQ ID NO. 237, SEQ ID NO. 239, SEQ ID NO. 241,and combinations thereof, and that has the light chain variable domainsequence that is at least 95% identical to the amino acid sequencesselected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ IDNO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ IDNO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34,SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO.44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ IDNO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72,SEQ ID NO. 74, SEQ ID NO. 76, SEQ ID NO. 78, SEQ ID NO. 80, SEQ ID NO.82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ IDNO. 92, SEQ ID NO. 94, SEQ ID NO. 96, SEQ ID NO. 98, SEQ ID NO. 100, SEQID NO. 102, SEQ ID NO. 104, SEQ ID NO. 106, SEQ ID NO. 108, SEQ ID NO.110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ ID NO. 116, SEQ ID NO. 118, SEQID NO. 120, SEQ ID NO. 122, SEQ ID NO. 124, SEQ ID NO. 126, SEQ ID NO.128, SEQ ID NO. 130, SEQ ID NO. 132, SEQ ID NO. 134, SEQ ID NO. 136, SEQID NO. 138, SEQ ID NO. 140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO.146, SEQ ID NO. 148, SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQID NO. 156, SEQ ID NO. 158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO.164, SEQ ID NO. 166, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO. 172, SEQID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO. 180, SEQ ID NO.182, SEQ ID NO. 184, SEQ ID NO. 186, SEQ ID NO. 188, SEQ ID NO. 190, SEQID NO. 192, SEQ ID NO. 194, SEQ ID NO. 196, SEQ ID NO. 198, SEQ ID NO.200, SEQ ID NO. 202, SEQ ID NO. 204, SEQ ID NO. 206, SEQ ID NO. 208, SEQID NO. 210, SEQ ID NO. 212, SEQ ID NO. 214, SEQ ID NO. 216, SEQ ID NO.218, SEQ ID NO. 220, SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQID NO. 228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO.236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO. 242, and combinationsthereof; and

wherein the single chain human antibody has the heavy chain variabledomain sequence that is at least 95% identical to the amino acidsequences selected from the group consisting of SEQ ID NO. 1, SEQ ID NO.3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO.13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ IDNO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQID NO. 33, SEQ ID NO. 35, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41,SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO.51, SEQ ID NO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ IDNO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQID NO. 71, SEQ ID NO. 73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO. 79,SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO.89, SEQ ID NO. 91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ IDNO. 99, SEQ ID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID NO. 107,SEQ ID NO. 109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115, SEQ IDNO. 117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ ID NO. 125,SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO. 133, SEQ IDNO. 135, SEQ ID NO. 137, SEQ ID NO. 139, SEQ ID NO. 141, SEQ ID NO. 143,SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO. 149, SEQ ID NO. 151, SEQ IDNO. 153, SEQ ID NO. 155, SEQ ID NO. 157, SEQ ID NO. 159, SEQ ID NO. 161,SEQ ID NO. 163, SEQ ID NO. 165, SEQ ID NO. 167, SEQ ID NO. 169, SEQ IDNO. 171, SEQ ID NO. 173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO. 179,SEQ ID NO. 181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO. 187, SEQ IDNO. 189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO. 197,SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO. 205, SEQ IDNO. 207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ ID NO. 213, SEQ ID NO. 215,SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO. 221, SEQ ID NO. 223, SEQ IDNO. 225, SEQ ID NO. 227, SEQ ID NO. 229, SEQ ID NO. 231, SEQ ID NO. 233,SEQ ID NO. 235, SEQ ID NO. 237, SEQ ID NO. 239, SEQ ID NO. 241, andcombinations thereof, and that has the light chain variable domainsequence that is at least 95% identical to the amino acid sequencesselected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ IDNO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ IDNO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34,SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO.44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ IDNO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72,SEQ ID NO. 74, SEQ ID NO. 76, SEQ ID NO. 78, SEQ ID NO. 80, SEQ ID NO.82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ IDNO. 92, SEQ ID NO. 94, SEQ ID NO. 96, SEQ ID NO. 98, SEQ ID NO. 100, SEQID NO. 102, SEQ ID NO. 104, SEQ ID NO. 106, SEQ ID NO. 108, SEQ ID NO.110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ ID NO. 116, SEQ ID NO. 118, SEQID NO. 120, SEQ ID NO. 122, SEQ ID NO. 124, SEQ ID NO. 126, SEQ ID NO.128, SEQ ID NO. 130, SEQ ID NO. 132, SEQ ID NO. 134, SEQ ID NO. 136, SEQID NO. 138, SEQ ID NO. 140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO.146, SEQ ID NO. 148, SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQID NO. 156, SEQ ID NO. 158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO.164, SEQ ID NO. 166, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO. 172, SEQID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO. 180, SEQ ID NO.182, SEQ ID NO. 184, SEQ ID NO. 186, SEQ ID NO. 188, SEQ ID NO. 190, SEQID NO. 192, SEQ ID NO. 194, SEQ ID NO. 196, SEQ ID NO. 198, SEQ ID NO.200, SEQ ID NO. 202, SEQ ID NO. 204, SEQ ID NO. 206, SEQ ID NO. 208, SEQID NO. 210, SEQ ID NO. 212, SEQ ID NO. 214, SEQ ID NO. 216, SEQ ID NO.218, SEQ ID NO. 220, SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQID NO. 228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO.236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO. 242, and combinationsthereof.

Preferably, the fully human antibody has both a heavy chain and a lightchain wherein the antibody has a heavy chain/light chain variable domainsequence selected from the group consisting of SEQ ID NO. 1/SEQ ID NO.2, SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO.7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID NO. 12,SEQ ID NO. 13/SEQ ID NO. 14, SEQ ID NO. 15/SEQ ID NO. 16, SEQ ID NO.17/SEQ ID NO. 18, SEQ ID NO. 19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO.22, SEQ ID NO. 23/SEQ ID NO. 24, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO.27/SEQ ID NO. 28, SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID NO.32, SEQ ID NO. 33/SEQ ID NO. 34, SEQ ID NO. 35/SEQ ID NO. 36, SEQ ID NO.37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ ID NO. 40, SEQ ID NO. 41/SEQ ID NO.42, SEQ ID NO. 43/SEQ ID NO. 44, SEQ ID NO. 45/SEQ ID NO. 46, SEQ ID NO.47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ ID NO. 50, SEQ ID NO. 51/SEQ ID NO.52, SEQ ID NO. 53/SEQ ID NO. 54, SEQ ID NO. 55/SEQ ID NO. 56, SEQ ID NO.57/SEQ ID NO. 58, SEQ ID NO. 59/SEQ ID NO. 60, SEQ ID NO. 61/SEQ ID NO.62, SEQ ID NO. 63/SEQ ID NO. 64, SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO.67/SEQ ID NO. 68, SEQ ID NO. 69/SEQ ID NO. 70, SEQ ID NO. 71/SEQ ID NO.72, SEQ ID NO. 73/SEQ ID NO. 74, SEQ ID NO. 75/SEQ ID NO. 76, SEQ ID NO.77/SEQ ID NO. 78, SEQ ID NO. 79/SEQ ID NO. 80, SEQ ID NO. 81/SEQ ID NO.82, SEQ ID NO. 83/SEQ ID NO. 84, SEQ ID NO. 85/SEQ ID NO. 86, SEQ ID NO.87/SEQ ID NO. 88, SEQ ID NO. 89/SEQ ID NO. 90, SEQ ID NO. 91/SEQ ID NO.92, SEQ ID NO. 93/SEQ ID NO. 94, SEQ ID NO. 95/SEQ ID NO. 96, SEQ ID NO.97/SEQ ID NO. 98, SEQ ID NO. 99/SEQ ID NO. 100, SEQ ID NO. 101/SEQ IDNO. 102, SEQ ID NO. 103/SEQ ID NO. 104, SEQ ID NO. 105/SEQ ID NO. 106,SEQ ID NO. 107/SEQ ID NO. 108, SEQ ID NO. 109/SEQ ID NO. 110, SEQ ID NO.111/SEQ ID NO. 112, SEQ ID NO. 113/SEQ ID NO. 114, SEQ ID NO. 115/SEQ IDNO. 116, SEQ ID NO. 117/SEQ ID NO. 118, SEQ ID NO. 119/SEQ ID NO. 120,SEQ ID NO. 121/SEQ ID NO. 122, SEQ ID NO. 123/SEQ ID NO. 124, SEQ ID NO.125/SEQ ID NO. 126, SEQ ID NO. 127/SEQ ID NO. 128, SEQ ID NO. 129/SEQ IDNO. 130, SEQ ID NO. 131/SEQ ID NO. 132, SEQ ID NO. 133/SEQ ID NO. 134,SEQ ID NO. 135/SEQ ID NO. 136, SEQ ID NO. 137/SEQ ID NO. 138, SEQ ID NO.139/SEQ ID NO. 140, SEQ ID NO. 141/SEQ ID NO. 142, SEQ ID NO. 143/SEQ IDNO. 144, SEQ ID NO. 145/SEQ ID NO. 146, SEQ ID NO. 147/SEQ ID NO. 148,SEQ ID NO. 149/SEQ ID NO. 150, SEQ ID NO. 151/SEQ ID NO. 152, SEQ ID NO.153/SEQ ID NO. 154, SEQ ID NO. 155/SEQ ID NO. 156, SEQ ID NO. 157/SEQ IDNO. 158, SEQ ID NO. 159/SEQ ID NO. 160, SEQ ID NO. 161/SEQ ID NO. 162,SEQ ID NO. 163/SEQ ID NO. 164, SEQ ID NO. 165/SEQ ID NO. 166, SEQ ID NO.167/SEQ ID NO. 168, SEQ ID NO. 169/SEQ ID NO. 170, SEQ ID NO. 171/SEQ IDNO. 172, SEQ ID NO. 173/SEQ ID NO. 174, SEQ ID NO. 175/SEQ ID NO. 176,SEQ ID NO. 177/SEQ ID NO. 178, SEQ ID NO. 179/SEQ ID NO. 180, SEQ ID NO.181/SEQ ID NO. 182, SEQ ID NO. 183/SEQ ID NO. 184, SEQ ID NO. 185/SEQ IDNO. 186, SEQ ID NO. 187/SEQ ID NO. 188, SEQ ID NO. 189/SEQ ID NO. 190,SEQ ID NO. 191/SEQ ID NO. 192, SEQ ID NO. 193/SEQ ID NO. 194, SEQ ID NO.195/SEQ ID NO. 196, SEQ ID NO. 197/SEQ ID NO. 198, SEQ ID NO. 199/SEQ IDNO. 200, SEQ ID NO. 201/SEQ ID NO. 202, SEQ ID NO. 203/SEQ ID NO. 204,SEQ ID NO. 205/SEQ ID NO. 206, SEQ ID NO. 207/SEQ ID NO. 208, SEQ ID NO.209/SEQ ID NO. 210, SEQ ID NO. 211/SEQ ID NO. 212, SEQ ID NO. 213/SEQ IDNO. 214, SEQ ID NO. 215/SEQ ID NO. 216, SEQ ID NO. 217/SEQ ID NO. 218,SEQ ID NO. 219/SEQ ID NO. 220, SEQ ID NO. 221/SEQ ID NO. 222, SEQ ID NO.223/SEQ ID NO. 224, SEQ ID NO. 225/SEQ ID NO. 226, SEQ ID NO. 227/SEQ IDNO. 228, SEQ ID NO. 229/SEQ ID NO. 230, SEQ ID NO. 231/SEQ ID NO. 232,SEQ ID NO. 233/SEQ ID NO. 234, SEQ ID NO. 235/SEQ ID NO. 236, SEQ ID NO.237/SEQ ID NO. 238, SEQ ID NO. 239/SEQ ID NO. 240, SEQ ID NO. 241/SEQ IDNO. 242, and combinations thereof. Preferably, the fully human antibodyFab fragment has both a heavy chain variable domain region and a lightchain variable domain region wherein the antibody has a heavychain/light chain variable domain sequence selected from the groupconsisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ IDNO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ IDNO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO. 19/SEQ IDNO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ ID NO. 24, SEQ IDNO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28, SEQ ID NO. 29/SEQ IDNO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID NO. 33/SEQ ID NO. 34, SEQ IDNO. 35/SEQ ID NO. 36, SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ IDNO. 40, SEQ ID NO. 41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ ID NO. 44, SEQ IDNO. 45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ IDNO. 50, SEQ ID NO. 51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ ID NO. 54, SEQ IDNO. 55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID NO. 59/SEQ IDNO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID NO. 64, SEQ IDNO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID NO. 68, SEQ ID NO. 69/SEQ IDNO. 70, SEQ ID NO. 71/SEQ ID NO. 72, SEQ ID NO. 73/SEQ ID NO. 74, SEQ IDNO. 75/SEQ ID NO. 76, SEQ ID NO. 77/SEQ ID NO. 78, SEQ ID NO. 79/SEQ IDNO. 80, SEQ ID NO. 81/SEQ ID NO. 82, SEQ ID NO. 83/SEQ ID NO. 84, SEQ IDNO. 85/SEQ ID NO. 86, SEQ ID NO. 87/SEQ ID NO. 88, SEQ ID NO. 89/SEQ IDNO. 90, SEQ ID NO. 91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ ID NO. 94, SEQ IDNO. 95/SEQ ID NO. 96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ ID NO. 99/SEQ IDNO. 100, SEQ ID NO. 101/SEQ ID NO. 102, SEQ ID NO. 103/SEQ ID NO. 104,SEQ ID NO. 105/SEQ ID NO. 106, SEQ ID NO. 107/SEQ ID NO. 108, SEQ ID NO.109/SEQ ID NO. 110, SEQ ID NO. 111/SEQ ID NO. 112, SEQ ID NO. 113/SEQ IDNO. 114, SEQ ID NO. 115/SEQ ID NO. 116, SEQ ID NO. 117/SEQ ID NO. 118,SEQ ID NO. 119/SEQ ID NO. 120, SEQ ID NO. 121/SEQ ID NO. 122, SEQ ID NO.123/SEQ ID NO. 124, SEQ ID NO. 125/SEQ ID NO. 126, SEQ ID NO. 127/SEQ IDNO. 128, SEQ ID NO. 129/SEQ ID NO. 130, SEQ ID NO. 131/SEQ ID NO. 132,SEQ ID NO. 133/SEQ ID NO. 134, SEQ ID NO. 135/SEQ ID NO. 136, SEQ ID NO.137/SEQ ID NO. 138, SEQ ID NO. 139/SEQ ID NO. 140, SEQ ID NO. 141/SEQ IDNO. 142, SEQ ID NO. 143/SEQ ID NO. 144, SEQ ID NO. 145/SEQ ID NO. 146,SEQ ID NO. 147/SEQ ID NO. 148, SEQ ID NO. 149/SEQ ID NO. 150, SEQ ID NO.151/SEQ ID NO. 152, SEQ ID NO. 153/SEQ ID NO. 154, SEQ ID NO. 155/SEQ IDNO. 156, SEQ ID NO. 157/SEQ ID NO. 158, SEQ ID NO. 159/SEQ ID NO. 160,SEQ ID NO. 161/SEQ ID NO. 162, SEQ ID NO. 163/SEQ ID NO. 164, SEQ ID NO.165/SEQ ID NO. 166, SEQ ID NO. 167/SEQ ID NO. 168, SEQ ID NO. 169/SEQ IDNO. 170, SEQ ID NO. 171/SEQ ID NO. 172, SEQ ID NO. 173/SEQ ID NO. 174,SEQ ID NO. 175/SEQ ID NO. 176, SEQ ID NO. 177/SEQ ID NO. 178, SEQ ID NO.179/SEQ ID NO. 180, SEQ ID NO. 181/SEQ ID NO. 182, SEQ ID NO. 183/SEQ IDNO. 184, SEQ ID NO. 185/SEQ ID NO. 186, SEQ ID NO. 187/SEQ ID NO. 188,SEQ ID NO. 189/SEQ ID NO. 190, SEQ ID NO. 191/SEQ ID NO. 192, SEQ ID NO.193/SEQ ID NO. 194, SEQ ID NO. 195/SEQ ID NO. 196, SEQ ID NO. 197/SEQ IDNO. 198, SEQ ID NO. 199/SEQ ID NO. 200, SEQ ID NO. 201/SEQ ID NO. 202,SEQ ID NO. 203/SEQ ID NO. 204, SEQ ID NO. 205/SEQ ID NO. 206, SEQ ID NO.207/SEQ ID NO. 208, SEQ ID NO. 209/SEQ ID NO. 210, SEQ ID NO. 211/SEQ IDNO. 212, SEQ ID NO. 213/SEQ ID NO. 214, SEQ ID NO. 215/SEQ ID NO. 216,SEQ ID NO. 217/SEQ ID NO. 218, SEQ ID NO. 219/SEQ ID NO. 220, SEQ ID NO.221/SEQ ID NO. 222, SEQ ID NO. 223/SEQ ID NO. 224, SEQ ID NO. 225/SEQ IDNO. 226, SEQ ID NO. 227/SEQ ID NO. 228, SEQ ID NO. 229/SEQ ID NO. 230,SEQ ID NO. 231/SEQ ID NO. 232, SEQ ID NO. 233/SEQ ID NO. 234, SEQ ID NO.235/SEQ ID NO. 236, SEQ ID NO. 237/SEQ ID NO. 238, SEQ ID NO. 239/SEQ IDNO. 240, SEQ ID NO. 241/SEQ ID NO. 242, and combinations thereof.Preferably, the fully human single chain antibody has both a heavy chainvariable domain region and a light chain variable domain region, whereinthe single chain fully human antibody has a heavy chain/light chainvariable domain sequence selected from the group consisting of SEQ IDNO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO. 5/SEQ ID NO.6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO. 10, SEQ ID NO.11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ ID NO. 15/SEQ ID NO.16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO. 19/SEQ ID NO. 20, SEQ ID NO.21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ ID NO. 24, SEQ ID NO. 25/SEQ ID NO.26, SEQ ID NO. 27/SEQ ID NO. 28, SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO.31/SEQ ID NO. 32, SEQ ID NO. 33/SEQ ID NO. 34, SEQ ID NO. 35/SEQ ID NO.36, SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ ID NO. 40, SEQ ID NO.41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ ID NO. 44, SEQ ID NO. 45/SEQ ID NO.46, SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ ID NO. 50, SEQ ID NO.51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ ID NO. 54, SEQ ID NO. 55/SEQ ID NO.56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID NO. 59/SEQ ID NO. 60, SEQ ID NO.61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID NO. 64, SEQ ID NO. 65/SEQ ID NO.66, SEQ ID NO. 67/SEQ ID NO. 68, SEQ ID NO. 69/SEQ ID NO. 70, SEQ ID NO.71/SEQ ID NO. 72, SEQ ID NO. 73/SEQ ID NO. 74, SEQ ID NO. 75/SEQ ID NO.76, SEQ ID NO. 77/SEQ ID NO. 78, SEQ ID NO. 79/SEQ ID NO. 80, SEQ ID NO.81/SEQ ID NO. 82, SEQ ID NO. 83/SEQ ID NO. 84, SEQ ID NO. 85/SEQ ID NO.86, SEQ ID NO. 87/SEQ ID NO. 88, SEQ ID NO. 89/SEQ ID NO. 90, SEQ ID NO.91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ ID NO. 94, SEQ ID NO. 95/SEQ ID NO.96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ ID NO. 99/SEQ ID NO. 100, SEQ IDNO. 101/SEQ ID NO. 102, SEQ ID NO. 103/SEQ ID NO. 104, SEQ ID NO.105/SEQ ID NO. 106, SEQ ID NO. 107/SEQ ID NO. 108, SEQ ID NO. 109/SEQ IDNO. 110, SEQ ID NO. 111/SEQ ID NO. 112, SEQ ID NO. 113/SEQ ID NO. 114,SEQ ID NO. 115/SEQ ID NO. 116, SEQ ID NO. 117/SEQ ID NO. 118, SEQ ID NO.119/SEQ ID NO. 120, SEQ ID NO. 121/SEQ ID NO. 122, SEQ ID NO. 123/SEQ IDNO. 124, SEQ ID NO. 125/SEQ ID NO. 126, SEQ ID NO. 127/SEQ ID NO. 128,SEQ ID NO. 129/SEQ ID NO. 130, SEQ ID NO. 131/SEQ ID NO. 132, SEQ ID NO.133/SEQ ID NO. 134, SEQ ID NO. 135/SEQ ID NO. 136, SEQ ID NO. 137/SEQ IDNO. 138, SEQ ID NO. 139/SEQ ID NO. 140, SEQ ID NO. 141/SEQ ID NO. 142,SEQ ID NO. 143/SEQ ID NO. 144, SEQ ID NO. 145/SEQ ID NO. 146, SEQ ID NO.147/SEQ ID NO. 148, SEQ ID NO. 149/SEQ ID NO. 150, SEQ ID NO. 151/SEQ IDNO. 152, SEQ ID NO. 153/SEQ ID NO. 154, SEQ ID NO. 155/SEQ ID NO. 156,SEQ ID NO. 157/SEQ ID NO. 158, SEQ ID NO. 159/SEQ ID NO. 160, SEQ ID NO.161/SEQ ID NO. 162, SEQ ID NO. 163/SEQ ID NO. 164, SEQ ID NO. 165/SEQ IDNO. 166, SEQ ID NO. 167/SEQ ID NO. 168, SEQ ID NO. 169/SEQ ID NO. 170,SEQ ID NO. 171/SEQ ID NO. 172, SEQ ID NO. 173/SEQ ID NO. 174, SEQ ID NO.175/SEQ ID NO. 176, SEQ ID NO. 177/SEQ ID NO. 178, SEQ ID NO. 179/SEQ IDNO. 180, SEQ ID NO. 181/SEQ ID NO. 182, SEQ ID NO. 183/SEQ ID NO. 184,SEQ ID NO. 185/SEQ ID NO. 186, SEQ ID NO. 187/SEQ ID NO. 188, SEQ ID NO.189/SEQ ID NO. 190, SEQ ID NO. 191/SEQ ID NO. 192, SEQ ID NO. 193/SEQ IDNO. 194, SEQ ID NO. 195/SEQ ID NO. 196, SEQ ID NO. 197/SEQ ID NO. 198,SEQ ID NO. 199/SEQ ID NO. 200, SEQ ID NO. 201/SEQ ID NO. 202, SEQ ID NO.203/SEQ ID NO. 204, SEQ ID NO. 205/SEQ ID NO. 206, SEQ ID NO. 207/SEQ IDNO. 208, SEQ ID NO. 209/SEQ ID NO. 210, SEQ ID NO. 211/SEQ ID NO. 212,SEQ ID NO. 213/SEQ ID NO. 214, SEQ ID NO. 215/SEQ ID NO. 216, SEQ ID NO.217/SEQ ID NO. 218, SEQ ID NO. 219/SEQ ID NO. 220, SEQ ID NO. 221/SEQ IDNO. 222, SEQ ID NO. 223/SEQ ID NO. 224, SEQ ID NO. 225/SEQ ID NO. 226,SEQ ID NO. 227/SEQ ID NO. 228, SEQ ID NO. 229/SEQ ID NO. 230, SEQ ID NO.231/SEQ ID NO. 232, SEQ ID NO. 233/SEQ ID NO. 234, SEQ ID NO. 235/SEQ IDNO. 236, SEQ ID NO. 237/SEQ ID NO. 238, SEQ ID NO. 239/SEQ ID NO. 240,SEQ ID NO. 241/SEQ ID NO. 242, and combinations thereof.

Preferably, the broad spectrum of mammalian cancers to be treated isselected from the group consisting of ovarian, colon, breast, lungcancers, myelomas, neuroblastic-derived CNS tumors, monocytic leukemias,B-cell derived leukemias, T-cell derived leukemias, B-cell derivedlymphomas, T-cell derived lymphomas, mast cell derived tumors, andcombinations thereof. Preferably, the autoimmune disease or inflammatorydisease is selected from the group consisting of intestinal mucosalinflammation, wasting disease associated with colitis, multiplesclerosis, systemic lupus erythematosus, viral infections, rheumatoidarthritis, osteoarthritis, psoriasis, Cohn's disease, and inflammatorybowel disease.

An “antigen binding protein” is a protein comprising a portion thatbinds to an antigen and, optionally, a scaffold or framework portionthat allows the antigen binding portion to adopt a conformation thatpromotes binding of the antigen binding protein to the antigen. Examplesof antigen binding proteins include antibodies, antibody fragments(e.g., an antigen binding portion of an antibody), antibody derivatives,and antibody analogs. The antigen binding protein can comprise, forexample, an alternative protein scaffold or artificial scaffold withgrafted CDRs or CDR derivatives. Such scaffolds include, but are notlimited to, antibody-derived scaffolds comprising mutations introducedto, for example, stabilize the three-dimensional structure of theantigen binding protein as well as wholly synthetic scaffoldscomprising, for example, a biocompatible polymer. See, for example,Korndorfer et al., 2003, Proteins: Structure, Function, andBioinformatics, Volume 53, Issue 1:121-129; Roque et al., 2004,Biotechnol. Prog. 20:639-654. In addition, peptide antibody mimetics(“PAMs”) can be used, as well as scaffolds based on antibody mimeticsutilizing fibronection components as a scaffold.

An antigen binding protein can have, for example, the structure of anaturally occurring immunoglobulin. An “immunoglobulin” is a tetramericmolecule. In a naturally occurring immunoglobulin, each tetramer iscomposed of two identical pairs of polypeptide chains, each pair havingone “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa). Theamino-terminal portion of each chain includes a variable region of about100 to 110 or more amino acids primarily responsible for antigenrecognition. The carboxy-terminal portion of each chain defines aconstant region primarily responsible for effector function. Human lightchains are classified as kappa or lambda light chains. Heavy chains areclassified as mu, delta, gamma, alpha, or epsilon, and define theantibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. Withinlight and heavy chains, the variable and constant regions are joined bya “J” region of about 12 or more amino acids, with the heavy chain alsoincluding a “D” region of about 10 more amino acids. See generally,Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y.(1989)) (incorporated by reference in its entirety for all purposes).The variable regions of each light/heavy chain pair form the antibodybinding site such that an intact immunoglobulin has two binding sites.

The variable regions of naturally occurring immunoglobulin chainsexhibit the same general structure of relatively conserved frameworkregions (FR) joined by three hypervariable regions, also calledcomplementarity determining regions or CDRs. From N-terminus toC-terminus, both light and heavy chains comprise the domains FR1, CDR1,FR2, CDR2, FR3, CDR3 and FR4. The assignment of amino acids to eachdomain is in accordance with the definitions of Kabat et al. inSequences of Proteins of Immunological Interest, 5^(th) Ed., US Dept. ofHealth and Human Services, PHS, NIH, NIH Publication no. 91-3242, 1991.Other numbering systems for the amino acids in immunoglobulin chainsinclude IMGT® (international ImMunoGeneTics information system; Lefrancet al, Dev. Comp. Immunol. 29:185-203; 2005) and AHo (Honegger andPluckthun, J. Mol. Biol. 309(3):657-670; 2001).

Antibodies can be obtained from sources such as serum or plasma thatcontain immunoglobulins having varied antigenic specificity. If suchantibodies are subjected to affinity purification, they can be enrichedfor a particular antigenic specificity. Such enriched preparations ofantibodies usually are made of less than about 10% antibody havingspecific binding activity for the particular antigen. Subjecting thesepreparations to several rounds of affinity purification can increase theproportion of antibody having specific binding activity for the antigen.Antibodies prepared in this manner are often referred to as“monospecific.” Monospecfic antibody preparations can be made up ofabout 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%,99%, or 99.9% antibody having specific binding activity for theparticular antigen.

An “antibody” refers to an intact immunoglobulin or to an antigenbinding portion thereof that competes with the intact antibody forspecific binding, unless otherwise specified. Antigen binding portionsmay be produced by recombinant DNA techniques or by enzymatic orchemical cleavage of intact antibodies. Antigen binding portionsinclude, inter alia, Fab, Fab′, F(ab′)₂, Fv, domain antibodies (dAbs),and complementarity determining region (CDR) fragments, single-chainantibodies (scFv), chimeric antibodies, diabodies, triabodies,tetrabodies, and polypeptides that contain at least a portion of animmunoglobulin that is sufficient to confer specific antigen binding tothe polypeptide.

A Fab fragment is a monovalent fragment having the V_(L), V_(H), C_(L)and C_(H1) domains; a F(ab′)₂ fragment is a bivalent fragment having twoFab fragments linked by a disulfide bridge at the hinge region; a Fdfragment has the V_(H) and C_(H1) domains; an Fv fragment has the V_(L)and V_(H) domains of a single arm of an antibody; and a dAb fragment hasa V_(H) domain, a V_(L) domain, or an antigen-binding fragment of aV_(H) or VL domain (U.S. Pat. Nos. 6,846,634; 6,696,245, US App. Pub.20/0202512; 2004/0202995; 2004/0038291; 2004/0009507; 2003/0039958, andWard et al., Nature 341:544-546, 1989).

A single-chain antibody (scFv) is an antibody in which a V_(L) and aV_(H) region are joined via a linker (e.g., a synthetic sequence ofamino acid residues) to form a continuous protein chain wherein thelinker is long enough to allow the protein chain to fold back on itselfand form a monovalent antigen binding site (see, e.g., Bird et al.,1988, Science 242:423-26 and Huston et al., 1988, Proc. Natl. Acad. Sci.USA 85:5879-83). Diabodies are bivalent antibodies comprising twopolypeptide chains, wherein each polypeptide chain comprises V_(H) andV_(L) domains joined by a linker that is too short to allow for pairingbetween two domains on the same chain, thus allowing each domain to pairwith a complementary domain on another polypeptide chain (see, e.g.,Holliger et al., 1993, Proc. Natl. Acad. Sci. USA 90:6444-48, and Poljaket al., 1994, Structure 2:1121-23). If the two polypeptide chains of adiabody are identical, then a diabody resulting from their pairing willhave two identical antigen binding sites. Polypeptide chains havingdifferent sequences can be used to make a diabody with two differentantigen binding sites. Similarly, tribodies and tetrabodies areantibodies comprising three and four polypeptide chains, respectively,and forming three and four antigen binding sites, respectively, whichcan be the same or different.

Complementarity determining regions (CDRs) and framework regions (FR) ofa given antibody may be identified using the system described by Kabatet al. supra; Lefranc et al., supra and/or Honegger and Pluckthun,supra. One or more CDRs may be incorporated into a molecule eithercovalently or noncovalently to make it an antigen binding protein. Anantigen binding protein may incorporate the CDR(s) as part of a largerpolypeptide chain, may covalently link the CDR(s) to another polypeptidechain, or may incorporate the CDR(s) noncovalently. The CDRs permit theantigen binding protein to specifically bind to a particular antigen ofinterest.

An antigen binding protein may have one or more binding sites. If thereis more than one binding site, the binding sites may be identical to oneanother or may be different. For example, a naturally occurring humanimmunoglobulin typically has two identical binding sites, while a“bispecific” or “bifunctional” antibody has two different binding sites.

The term “human antibody” includes all antibodies that have one or morevariable and constant regions derived from human immunoglobulinsequences. In one embodiment, all of the variable and constant domainsare derived from human immunoglobulin sequences (a fully humanantibody). These antibodies may be prepared in a variety of ways,examples of which are described below, including through theimmunization with an antigen of interest of a mouse that is geneticallymodified to express antibodies derived from human heavy and/or lightchain-encoding genes.

A humanized antibody has a sequence that differs from the sequence of anantibody derived from a non-human species by one or more amino acidsubstitutions, deletions, and/or additions, such that the humanizedantibody is less likely to induce an immune response, and/or induces aless severe immune response, as compared to the non-human speciesantibody, when it is administered to a human subject. In one embodiment,certain amino acids in the framework and constant domains of the heavyand/or light chains of the non-human species antibody are mutated toproduce the humanized antibody. In another embodiment, the constantdomain(s) from a human antibody are fused to the variable domain(s) of anon-human species. In another embodiment, one or more amino acidresidues in one or more CDR sequences of a non-human antibody arechanged to reduce the likely immunogenicity of the non-human antibodywhen it is administered to a human subject, wherein the changed aminoacid residues either are not critical for immunospecific binding of theantibody to its antigen, or the changes to the amino acid sequence thatare made are conservative changes, such that the binding of thehumanized antibody to the antigen is not significantly worse than thebinding of the non-human antibody to the antigen. Examples of how tomake humanized antibodies may be found in U.S. Pat. Nos. 6,054,297,5,886,152 and 5,877,293.

The term “chimeric antibody” refers to an antibody that contains one ormore regions from one antibody and one or more regions from one or moreother antibodies. In one embodiment, one or more of the CDRs are derivedfrom a human anti-PD-L1 antibody. In another embodiment, all of the CDRsare derived from a human anti-PD-L1 antibody. In another embodiment, theCDRs from more than one human anti-PD-L1 antibodies are mixed andmatched in a chimeric antibody. For instance, a chimeric antibody maycomprise a CDR1 from the light chain of a first human anti-PAR-2antibody, a CDR2 and a CDR3 from the light chain of a second humananti-PD-L1 antibody, and the CDRs from the heavy chain from a thirdanti-PD-L1 antibody. Other combinations are possible.

Further, the framework regions may be derived from one of the sameanti-PD-L1 antibodies, from one or more different antibodies, such as ahuman antibody, or from a humanized antibody. In one example of achimeric antibody, a portion of the heavy and/or light chain isidentical with, homologous to, or derived from an antibody from aparticular species or belonging to a particular antibody class orsubclass, while the remainder of the chain(s) is/are identical with,homologous to, or derived from an antibody (-ies) from another speciesor belonging to another antibody class or subclass. Also included arefragments of such antibodies that exhibit the desired biologicalactivity (i.e., the ability to specifically bind PD-L1).

A “neutralizing antibody” or an “inhibitory antibody” is an antibodythat inhibits the proteolytic activation of PD-L1 when an excess of theanti-PD-L1 antibody reduces the amount of activation by at least about20% using an assay such as those described herein in the Examples. Invarious embodiments, the antigen binding protein reduces the amount ofamount of proteolytic activation of PD-L1 by at least 30%, 40%, 50%,60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, and 99.9%.

Fragments or analogs of antibodies can be readily prepared by those ofordinary skill in the art following the teachings of this specificationand using techniques known in the art. Preferred amino- andcarboxy-termini of fragments or analogs occur near boundaries offunctional domains. Structural and functional domains can be identifiedby comparison of the nucleotide and/or amino acid sequence data topublic or proprietary sequence databases. Computerized comparisonmethods can be used to identify sequence motifs or predicted proteinconformation domains that occur in other proteins of known structureand/or function. Methods to identify protein sequences that fold into aknown three-dimensional structure are known. See, Bowie et al., 1991,Science 253:164.

A “CDR grafted antibody” is an antibody comprising one or more CDRsderived from an antibody of a particular species or isotype and theframework of another antibody of the same or different species orisotype.

A “multi-specific antibody” is an antibody that recognizes more than oneepitope on one or more antigens. A subclass of this type of antibody isa “bi-specific antibody” which recognizes two distinct epitopes on thesame or different antigens.

An antigen binding protein “specifically binds” to an antigen (e.g.,human PD-L1) if it binds to the antigen with a dissociation constant of1 nanomolar or less.

An “antigen binding domain,” “antigen binding region,” or “antigenbinding site” is a portion of an antigen binding protein that containsamino acid residues (or other moieties) that interact with an antigenand contribute to the antigen binding protein's specificity and affinityfor the antigen. For an antibody that specifically binds to its antigen,this will include at least part of at least one of its CDR domains.

An “epitope” is the portion of a molecule that is bound by an antigenbinding protein (e.g., by an antibody). An epitope can comprisenon-contiguous portions of the molecule (e.g., in a polypeptide, aminoacid residues that are not contiguous in the polypeptide's primarysequence but that, in the context of the polypeptide's tertiary andquaternary structure, are near enough to each other to be bound by anantigen binding protein).

The “percent identity” of two polynucleotide or two polypeptidesequences is determined by comparing the sequences using the GAPcomputer program (a part of the GCG Wisconsin Package, version 10.3(Accelrys, San Diego, Calif.)) using its default parameters.

The terms “polynucleotide,” “oligonucleotide” and “nucleic acid” areused interchangeably throughout and include DNA molecules (e.g., cDNA orgenomic DNA), RNA molecules (e.g., mRNA), analogs of the DNA or RNAgenerated using nucleotide analogs (e.g., peptide nucleic acids andnon-naturally occurring nucleotide analogs), and hybrids thereof. Thenucleic acid molecule can be single-stranded or double-stranded. In oneembodiment, the nucleic acid molecules of the invention comprise acontiguous open reading frame encoding an antibody, or a fragment,derivative, mutein, or variant thereof.

Two single-stranded polynucleotides are “the complement” of each otherif their sequences can be aligned in an anti-parallel orientation suchthat every nucleotide in one polynucleotide is opposite itscomplementary nucleotide in the other polynucleotide, without theintroduction of gaps, and without unpaired nucleotides at the 5′ or the3′ end of either sequence. A polynucleotide is “complementary” toanother polynucleotide if the two polynucleotides can hybridize to oneanother under moderately stringent conditions. Thus, a polynucleotidecan be complementary to another polynucleotide without being itscomplement.

A “vector” is a nucleic acid that can be used to introduce anothernucleic acid linked to it into a cell. One type of vector is a“plasmid,” which refers to a linear or circular double stranded DNAmolecule into which additional nucleic acid segments can be ligated.Another type of vector is a viral vector (e.g., replication defectiveretroviruses, adenoviruses and adeno-associated viruses), whereinadditional DNA segments can be introduced into the viral genome. Certainvectors are capable of autonomous replication in a host cell into whichthey are introduced (e.g., bacterial vectors comprising a bacterialorigin of replication and episomal mammalian vectors). Other vectors(e.g., non-episomal mammalian vectors) are integrated into the genome ofa host cell upon introduction into the host cell, and thereby arereplicated along with the host genome. An “expression vector” is a typeof vector that can direct the expression of a chosen polynucleotide.

A nucleotide sequence is “operably linked” to a regulatory sequence ifthe regulatory sequence affects the expression (e.g., the level, timing,or location of expression) of the nucleotide sequence. A “regulatorysequence” is a nucleic acid that affects the expression (e.g., thelevel, timing, or location of expression) of a nucleic acid to which itis operably linked. The regulatory sequence can, for example, exert itseffects directly on the regulated nucleic acid, or through the action ofone or more other molecules (e.g., polypeptides that bind to theregulatory sequence and/or the nucleic acid). Examples of regulatorysequences include promoters, enhancers and other expression controlelements (e.g., polyadenylation signals). Further examples of regulatorysequences are described in, for example, Goeddel, 1990, Gene ExpressionTechnology: Methods in Enzymology 185, Academic Press, San Diego, Calif.and Baron et al., 1995, Nucleic Acids Res. 23:3605-06.

A “host cell” is a cell that can be used to express a nucleic acid,e.g., a nucleic acid of the invention. A host cell can be a prokaryote,for example, E. coli, or it can be a eukaryote, for example, asingle-celled eukaryote (e.g., a yeast or other fungus), a plant cell(e.g., a tobacco or tomato plant cell), an animal cell (e.g., a humancell, a monkey cell, a hamster cell, a rat cell, a mouse cell, or aninsect cell) or a hybridoma. Examples of host cells include the COS-7line of monkey kidney cells (ATCC CRL 1651) (see Gluzman et al., 1981,Cell 23:175), L cells, C127 cells, 3T3 cells (ATCC CCL 163), Chinesehamster ovary (CHO) cells or their derivatives such as Veggie CHO andrelated cell lines which grow in serum-free media (see Rasmussen et al.,1998, Cytotechnology 28:31) or CHO strain DX-B11, which is deficient inDHFR (see Urlaub et al., 1980, Proc. Natl. Acad. Sci. USA 77:4216-20),HeLa cells, BHK (ATCC CRL 10) cell lines, the CV1/EBNA cell line derivedfrom the African green monkey kidney cell line CV1 (ATCC CCL 70) (seeMcMahan et al., 1991, EMBO J. 10:2821), human embryonic kidney cellssuch as 293,293 EBNA or MSR 293, human epidermal A431 cells, humanColo205 cells, other transformed primate cell lines, normal diploidcells, cell strains derived from in vitro culture of primary tissue,primary explants, HL-60, U937, HaK or Jurkat cells. Typically, a hostcell is a cultured cell that can be transformed or transfected with apolypeptide-encoding nucleic acid, which can then be expressed in thehost cell. The phrase “recombinant host cell” can be used to denote ahost cell that has been transformed or transfected with a nucleic acidto be expressed. A host cell also can be a cell that comprises thenucleic acid but does not express it at a desired level unless aregulatory sequence is introduced into the host cell such that itbecomes operably linked with the nucleic acid. It is understood that theterm host cell refers not only to the particular subject cell but alsoto the progeny or potential progeny of such a cell. Because certainmodifications may occur in succeeding generations due to, e.g., mutationor environmental influence, such progeny may not, in fact, be identicalto the parent cell, but are still included within the scope of the termas used herein.

Preferably, the mammalian cancer to be treated is selected from thegroup consisting of ovarian, colon, breast or hepatic carcinoma celllines, myelomas, neuroblastic-derived CNS tumors, monocytic leukemias,B-cell derived leukemia's, T-cell derived leukemias, B-cell derivedlymphomas, T-cell derived lymphomas, mast cell derived tumors, andcombinations thereof.

Polypeptides of the present disclosure can be produced using anystandard methods known in the art. In one example, the polypeptides areproduced by recombinant DNA methods by inserting a nucleic acid sequence(e.g., a cDNA) encoding the polypeptide into a recombinant expressionvector and expressing the DNA sequence under conditions promotingexpression.

Nucleic acids encoding any of the various polypeptides disclosed hereinmay be synthesized chemically. Codon usage may be selected so as toimprove expression in a cell. Such codon usage will depend on the celltype selected. Specialized codon usage patterns have been developed forE. coli and other bacteria, as well as mammalian cells, plant cells,yeast cells and insect cells. See for example: Mayfield et al., Proc.Natl. Acad. Sci. USA. 2003 100(2):438-42; Sinclair et al. Protein Expr.Purif. 2002 (1):96-105; Connell N D. Curr. Opin. Biotechnol. 200112(5):446-9; Makrides et al. Microbiol. Rev. 1996 60(3):512-38; andSharp et al. Yeast. 1991 7(7):657-78.

General techniques for nucleic acid manipulation are described forexample in Sambrook et al., Molecular Cloning: A Laboratory Manual,Vols. 1-3, Cold Spring Harbor Laboratory Press, 2 ed., 1989, or F.Ausubel et al., Current Protocols in Molecular Biology (Green Publishingand Wiley-Interscience: New York, 1987) and periodic updates, hereinincorporated by reference. The DNA encoding the polypeptide is operablylinked to suitable transcriptional or translational regulatory elementsderived from mammalian, viral, or insect genes. Such regulatory elementsinclude a transcriptional promoter, an optional operator sequence tocontrol transcription, a sequence encoding suitable mRNA ribosomalbinding sites, and sequences that control the termination oftranscription and translation. The ability to replicate in a host,usually conferred by an origin of replication, and a selection gene tofacilitate recognition of transformants is additionally incorporated.

The recombinant DNA can also include any type of protein tag sequencethat may be useful for purifying the protein. Examples of protein tagsinclude but are not limited to a histidine tag, a FLAG tag, a myc tag,an HA tag, or a GST tag. Appropriate cloning and expression vectors foruse with bacterial, fungal, yeast, and mammalian cellular hosts can befound in Cloning Vectors: A Laboratory Manual, (Elsevier, N.Y., 1985).

The expression construct is introduced into the host cell using a methodappropriate to the host cell. A variety of methods for introducingnucleic acids into host cells are known in the art, including, but notlimited to, electroporation; transfection employing calcium chloride,rubidium chloride, calcium phosphate, DEAE-dextran, or other substances;microprojectile bombardment; lipofection; and infection (where thevector is an infectious agent). Suitable host cells include prokaryotes,yeast, mammalian cells, or bacterial cells.

Suitable bacteria include gram negative or gram positive organisms, forexample, E. coli or Bacillus spp. Yeast, preferably from theSaccharomyces species, such as S. cerevisiae, may also be used forproduction of polypeptides. Various mammalian or insect cell culturesystems can also be employed to express recombinant proteins.Baculovirus systems for production of heterologous proteins in insectcells are reviewed by Luckow and Summers, (Bio/Technology, 6:47, 1988).Examples of suitable mammalian host cell lines include endothelialcells, COS-7 monkey kidney cells, CV-1, L cells, C127, 3T3, Chinesehamster ovary (CHO), human embryonic kidney cells, HeLa, 293, 293T, andBHK cell lines. Purified polypeptides are prepared by culturing suitablehost/vector systems to express the recombinant proteins. For manyapplications, the small size of many of the polypeptides disclosedherein would make expression in E. coli as the preferred method forexpression. The protein is then purified from culture media or cellextracts.

Proteins disclosed herein can also be produced using cell-translationsystems. For such purposes the nucleic acids encoding the polypeptidemust be modified to allow in vitro transcription to produce mRNA and toallow cell-free translation of the mRNA in the particular cell-freesystem being utilized (eukaryotic such as a mammalian or yeast cell-freetranslation system or prokaryotic such as a bacterial cell-freetranslation system.

PD-L1-binding polypeptides can also be produced by chemical synthesis(e.g., by the methods described in Solid Phase Peptide Synthesis, 2nded., 1984, The Pierce Chemical Co., Rockford, Ill.). Modifications tothe protein can also be produced by chemical synthesis.

The polypeptides of the present disclosure can be purified byisolation/purification methods for proteins generally known in the fieldof protein chemistry. Non-limiting examples include extraction,recrystallization, salting out (e.g., with ammonium sulfate or sodiumsulfate), centrifugation, dialysis, ultrafiltration, adsorptionchromatography, ion exchange chromatography, hydrophobic chromatography,normal phase chromatography, reversed-phase chromatography, gelfiltration, gel permeation chromatography, affinity chromatography,electrophoresis, countercurrent distribution or any combinations ofthese. After purification, polypeptides may be exchanged into differentbuffers and/or concentrated by any of a variety of methods known to theart, including, but not limited to, filtration and dialysis.

The purified polypeptide is preferably at least 85% pure, morepreferably at least 95% pure, and most preferably at least 98% pure.Regardless of the exact numerical value of the purity, the polypeptideis sufficiently pure for use as a pharmaceutical product.

Post-Translational Modifications of Polypeptides

In certain embodiments, the binding polypeptides of the invention mayfurther comprise post-translational modifications. Exemplarypost-translational protein modifications include phosphorylation,acetylation, methylation, ADP-ribosylation, ubiquitination,glycosylation, carbonylation, sumoylation, biotinylation or addition ofa polypeptide side chain or of a hydrophobic group. As a result, themodified soluble polypeptides may contain non-amino acid elements, suchas lipids, poly- or mono-saccharide, and phosphates. A preferred form ofglycosylation is sialylation, which conjugates one or more sialic acidmoieties to the polypeptide. Sialic acid moieties improve solubility andserum half-life while also reducing the possible immunogeneticity of theprotein. See Raju et al. Biochemistry. 2001 31; 40(30):8868-76. Effectsof such non-amino acid elements on the functionality of a polypeptidemay be tested for its antagonizing role in PD-L1 or PD-1 function, e.g.,its inhibitory effect on angiogenesis or on tumor growth.

In one specific embodiment, modified forms of the subject solublepolypeptides comprise linking the subject soluble polypeptides tononproteinaceous polymers. In one specific embodiment, the polymer ispolyethylene glycol (“PEG”), polypropylene glycol, or polyoxyalkylenes,in the manner as set forth in U.S. Pat. Nos. 4,640,835; 4,496,689;4,301,144; 4,670,417; 4,791,192 or 4,179,337.

PEG is a water soluble polymer that is commercially available or can beprepared by ring-opening polymerization of ethylene glycol according tomethods well known in the art (Sandler and Karo, Polymer Synthesis,Academic Press, New York, Vol. 3, pages 138-161). The term “PEG” is usedbroadly to encompass any polyethylene glycol molecule, without regard tosize or to modification at an end of the PEG, and can be represented bythe formula: X—O(CH₂CH₂O)_(n)-1CH₂CH₂OH (1), where n is 20 to 2300 and Xis H or a terminal modification, e.g., a C₁₋₄ alkyl. In one embodiment,the PEG of the invention terminates on one end with hydroxy or methoxy,i.e., X is H or CH₃ (“methoxy PEG”). A PEG can contain further chemicalgroups which are necessary for binding reactions; which results from thechemical synthesis of the molecule; or which is a spacer for optimaldistance of parts of the molecule. In addition, such a PEG can consistof one or more PEG side-chains which are linked together. PEGs with morethan one PEG chain are called multiarmed or branched PEGs. Branched PEGscan be prepared, for example, by the addition of polyethylene oxide tovarious polyols, including glycerol, pentaerythriol, and sorbitol. Forexample, a four-armed branched PEG can be prepared from pentaerythrioland ethylene oxide. Branched PEG are described in, for example, EP-A 0473 084 and U.S. Pat. No. 5,932,462. One form of PEGs includes two PEGside-chains (PEG2) linked via the primary amino groups of a lysine(Monfardini et al., Bioconjugate Chem. 6 (1995) 62-69).

Although PEG is well-known, this is, to our knowledge, the firstdemonstration that a pegylated^(10F)n3 polypeptide can be pegylated andretain ligand binding activity. In a preferred embodiment, thepegylated^(10F)n3 polypeptide is produced by site-directed pegylation,particularly by conjugation of PEG to a cysteine moiety at the N- orC-terminus. Accordingly, the present disclosure provides atarget-binding ^(10F)n3 polypeptide with improved pharmacokineticproperties, the polypeptide comprising: a ^(10F)n3 domain having fromabout 80 to about 150 amino acids, wherein at least one of the loops ofsaid ^(10F)n3 domain participate in target binding; and a covalentlybound PEG moiety, wherein said ^(10F)n3 polypeptide binds to the targetwith a K_(D) of less than 100 nM and has a clearance rate of less than30 mL/hr/kg in a mammal. The PEG moiety may be attached to the ^(10F)n3polypeptide by site directed pegylation, such as by attachment to a Cysresidue, where the Cys residue may be positioned at the N-terminus ofthe ^(0F)n3 polypeptide or between the N-terminus and the mostN-terminal beta or beta-like strand or at the C-terminus of the ^(10F)n3polypeptide or between the C-terminus and the most C-terminal beta orbeta-like strand. A Cys residue may be situated at other positions aswell, particularly any of the loops that do not participate in targetbinding. A PEG moiety may also be attached by other chemistry, includingby conjugation to amines.

PEG conjugation to peptides or proteins generally involves theactivation of PEG and coupling of the activated PEG-intermediatesdirectly to target proteins/peptides or to a linker, which issubsequently activated and coupled to target proteins/peptides (seeAbuchowski et al., J. Biol. Chem., 252, 3571 (1977) and J. Biol. Chem.,252, 3582 (1977), Zalipsky, et al., and Harris et. al., in:Poly(ethylene glycol) Chemistry: Biotechnical and BiomedicalApplications; (J. M. Harris ed.) Plenum Press: New York, 1992; Chap. 21and 22). It is noted that a binding polypeptide containing a PEGmolecule is also known as a conjugated protein, whereas the proteinlacking an attached PEG molecule can be referred to as unconjugated.

A variety of molecular mass forms of PEG can be selected, e.g., fromabout 1,000 Daltons (Da) to 100,000 Da (n is 20 to 2300), forconjugating to PD-L1-binding polypeptides. The number of repeating units“n” in the PEG is approximated for the molecular mass described inDaltons. It is preferred that the combined molecular mass of PEG on anactivated linker is suitable for pharmaceutical use. Thus, in oneembodiment, the molecular mass of the PEG molecules does not exceed100,000 Da. For example, if three PEG molecules are attached to alinker, where each PEG molecule has the same molecular mass of 12,000 Da(each n is about 270), then the total molecular mass of PEG on thelinker is about 36,000 Da (total n is about 820). The molecular massesof the PEG attached to the linker can also be different, e.g., of threemolecules on a linker two PEG molecules can be 5,000 Da each (each n isabout 110) and one PEG molecule can be 12,000 Da (n is about 270).

In a specific embodiment of the disclosure an PD-L1 binding polypeptideis covalently linked to one poly(ethylene glycol) group of the formula:—CO—(CH₂)_(x)—(OCH₂CH₂)_(m)—OR, with the —CO (i.e. carbonyl) of thepoly(ethylene glycol) group forming an amide bond with one of the aminogroups of the binding polypeptide; R being lower alkyl; x being 2 or 3;m being from about 450 to about 950; and n and m being chosen so thatthe molecular weight of the conjugate minus the binding polypeptide isfrom about 10 to 40 kDa. In one embodiment, a binding polypeptide's6-amino group of a lysine is the available (free) amino group.

The above conjugates may be more specifically presented by formula (II):P—NHCO—(CH₂)_(x)—(OCH₂CH₂)_(m)—OR (II), wherein P is the group of abinding polypeptide as described herein, (i.e. without the amino groupor amino groups which form an amide linkage with the carbonyl shown informula (II); and wherein R is lower alkyl; x is 2 or 3; m is from about450 to about 950 and is chosen so that the molecular weight of theconjugate minus the binding polypeptide is from about 10 to about 40kDa. As used herein, the given ranges of “m” have an orientationalmeaning. The ranges of “m” are determined in any case, and exactly, bythe molecular weight of the PEG group.

One skilled in the art can select a suitable molecular mass for PEG,e.g., based on how the pegylated binding polypeptide will be usedtherapeutically, the desired dosage, circulation time, resistance toproteolysis, immunogenicity, and other considerations. For a discussionof PEG and its use to enhance the properties of proteins, see Katre,Advanced Drug Delivery Reviews 10: 91-114 (1993).

In one embodiment, PEG molecules may be activated to react with aminogroups on a binding polypeptide, such as with lysines (Bencham et al.,Anal. Biochem., 131, 25 (1983); Veronese et al., Appl. Biochem., 11, 141(1985); Zalipsky et al., Polymeric Drugs and Drug Delivery Systems, adrs9-110 ACS Symposium Series 469 (1999); Zalipsky et al., Europ. Polym.J., 19, 1177-1183 (1983); Delgado et al., Biotechnology and AppliedBiochemistry, 12, 119-128 (1990)).

In one specific embodiment, carbonate esters of PEG are used to form thePEG-binding polypeptide conjugates. N,N′-disuccinimidylcarbonate (DSC)may be used in the reaction with PEG to form active mixedPEG-succinimidyl carbonate that may be subsequently reacted with anucleophilic group of a linker or an amino group of a bindingpolypeptide (see U.S. Pat. Nos. 5,281,698 and 5,932,462). In a similartype of reaction, 1,1′-(dibenzotriazolyl)carbonate anddi-(2-pyridyl)carbonate may be reacted with PEG to formPEG-benzotriazolyl and PEG-pyridyl mixed carbonate (U.S. Pat. No.5,382,657), respectively.

Pegylation of a ^(10F)n3 polypeptide can be performed according to themethods of the state of the art, for example by reaction of the bindingpolypeptide with electrophilically active PEGs (supplier: ShearwaterCorp., USA, www.shearwatercorp.com). Preferred PEG reagents of thepresent invention are, e.g., N-hydroxysuccinimidyl propionates(PEG-SPA), butanoates (PEG-SBA), PEG-succinimidyl propionate or branchedN-hydroxysuccinimides such as mPEG2-NHS (Monfardini et al., BioconjugateChem. 6 (1995) 62-69). Such methods may used to pegylated at an f-aminogroup of a binding polypeptide lysine or the N-terminal amino group ofthe binding polypeptide.

In another embodiment, PEG molecules may be coupled to sulfhydryl groupson a binding polypeptide (Sartore et al., Appl. Biochem. Biotechnol.,27, 45 (1991); Morpurgo et al., Biocon. Chem., 7, 363-368 (1996);Goodson et al., Bio/Technology (1990) 8, 343; U.S. Pat. No. 5,766,897).U.S. Pat. Nos. 6,610,281 and 5,766,897 describes exemplary reactive PEGspecies that may be coupled to sulfhydryl groups.

In some embodiments where PEG molecules are conjugated to cysteineresidues on a binding polypeptide, the cysteine residues are native tothe binding polypeptide, whereas in other embodiments, one or morecysteine residues are engineered into the binding polypeptide. Mutationsmay be introduced into a binding polypeptide coding sequence to generatecysteine residues. This might be achieved, for example, by mutating oneor more amino acid residues to cysteine. Preferred amino acids formutating to a cysteine residue include serine, threonine, alanine andother hydrophilic residues. Preferably, the residue to be mutated tocysteine is a surface-exposed residue. Algorithms are well-known in theart for predicting surface accessibility of residues based on primarysequence or a protein. Alternatively, surface residues may be predictedby comparing the amino acid sequences of binding polypeptides, giventhat the crystal structure of the framework based on which bindingpolypeptides are designed and evolved has been solved (see Himanen etal., Nature. (2001) 20-27; 414(6866):933-8) and thus the surface-exposedresidues identified. In one embodiment, cysteine residues are introducedinto binding polypeptides at or near the N- and/or C-terminus, or withinloop regions.

In some embodiments, the pegylated binding polypeptide comprises a PEGmolecule covalently attached to the alpha amino group of the N-terminalamino acid. Site specific N-terminal reductive amination is described inPepinsky et al., (2001) JPET, 297, 1059, and U.S. Pat. No. 5,824,784.The use of a PEG-aldehyde for the reductive amination of a proteinutilizing other available nucleophilic amino groups is described in U.S.Pat. No. 4,002,531, in Wieder et al., (1979) J. Biol. Chem. 254, 12579,and in Chamow et al., (1994) Bioconjugate Chem. 5, 133.

In another embodiment, pegylated binding polypeptide comprises one ormore PEG molecules covalently attached to a linker, which in turn isattached to the alpha amino group of the amino acid residue at theN-terminus of the binding polypeptide. Such an approach is disclosed inU.S. Patent Publication 2002/0044921 and in WO094/01451.

In one embodiment, a binding polypeptide is pegylated at the C-terminus.In a specific embodiment, a protein is pegylated at the C-terminus bythe introduction of C-terminal azido-methionine and the subsequentconjugation of a methyl-PEG-triarylphosphine compound via the Staudingerreaction. This C-terminal conjugation method is described in Cazalis etal., Bioconjug. Chem. 2004; 15(5):1005-1009.

Monopegylation of a binding polypeptide can also be produced accordingto the general methods described in WO 94/01451. WO 94/01451 describes amethod for preparing a recombinant polypeptide with a modified terminalamino acid alpha-carbon reactive group. The steps of the method involveforming the recombinant polypeptide and protecting it with one or morebiologically added protecting groups at the N-terminal alpha-amine andC-terminal alpha-carboxyl. The polypeptide can then be reacted withchemical protecting agents to selectively protect reactive side chaingroups and thereby prevent side chain groups from being modified. Thepolypeptide is then cleaved with a cleavage reagent specific for thebiological protecting group to form an unprotected terminal amino acidalpha-carbon reactive group. The unprotected terminal amino acidalpha-carbon reactive group is modified with a chemical modifying agent.The side chain protected terminally modified single copy polypeptide isthen deprotected at the side chain groups to form a terminally modifiedrecombinant single copy polypeptide. The number and sequence of steps inthe method can be varied to achieve selective modification at the N-and/or C-terminal amino acid of the polypeptide.

The ratio of a binding polypeptide to activated PEG in the conjugationreaction can be from about 1:0.5 to 1:50, between from about 1:1 to1:30, or from about 1:5 to 1:15. Various aqueous buffers can be used inthe present method to catalyze the covalent addition of PEG to thebinding polypeptide. In one embodiment, the pH of a buffer used is fromabout 7.0 to 9.0. In another embodiment, the pH is in a slightly basicrange, e.g., from about 7.5 to 8.5. Buffers having a pKa close toneutral pH range may be used, e.g., phosphate buffer.

Conventional separation and purification techniques known in the art canbe used to purify PEGylated binding polypeptide, such as size exclusion(e.g. gel filtration) and ion exchange chromatography. Products may alsobe separated using SDS-PAGE. Products that may be separated includemono-, di-, tri- poly- and un-pegylated binding polypeptide, as well asfree PEG. The percentage of mono-PEG conjugates can be controlled bypooling broader fractions around the elution peak to increase thepercentage of mono-PEG in the composition. About ninety percent mono-PEGconjugates represents a good balance of yield and activity. Compositionsin which, for example, at least ninety-two percent or at leastninety-six percent of the conjugates are mono-PEG species may bedesired. In an embodiment of this invention the percentage of mono-PEGconjugates is from ninety percent to ninety-six percent.

In one embodiment, PEGylated binding polypeptide of the inventioncontain one, two or more PEG moieties. In one embodiment, the PEGmoiety(ies) are bound to an amino acid residue which is on the surfaceof the protein and/or away from the surface that contacts the targetligand. In one embodiment, the combined or total molecular mass of PEGin PEG-binding polypeptide is from about 3,000 Da to 60,000 Da,optionally from about 10,000 Da to 36,000 Da. In a one embodiment, thePEG in pegylated binding polypeptide is a substantially linear,straight-chain PEG.

In one embodiment of the invention, the PEG in pegylated bindingpolypeptide is not hydrolyzed from the pegylated amino acid residueusing a hydroxylamine assay, e.g., 450 mM hydroxylamine (pH 6.5) over 8to 16 hours at room temperature, and is thus stable. In one embodiment,greater than 80% of the composition is stable mono-PEG-bindingpolypeptide, more preferably at least 90%, and most preferably at least95%.

In another embodiment, the pegylated binding polypeptides of theinvention will preferably retain at least 25%, 50%, 60%, 70%, 80%, 85%,90%, 95% or 100% of the biological activity associated with theunmodified protein. In one embodiment, biological activity refers to itsability to bind to PD-L1, as assessed by KD, k_(on) or k_(off). In onespecific embodiment, the pegylated binding polypeptide protein shows anincrease in binding to PD-L1 relative to unpegylated bindingpolypeptide.

The serum clearance rate of PEG-modified polypeptide may be decreased byabout 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or even 90%, relative tothe clearance rate of the unmodified binding polypeptide. ThePEG-modified polypeptide may have a half-life (t_(1/2)) which isenhanced relative to the half-life of the unmodified protein. Thehalf-life of PEG-binding polypeptide may be enhanced by at least 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%,250%, 300%, 400% or 500%, or even by 1000% relative to the half-life ofthe unmodified binding polypeptide. In some embodiments, the proteinhalf-life is determined in vitro, such as in a buffered saline solutionor in serum. In other embodiments, the protein half-life is an in vivohalf life, such as the half-life of the protein in the serum or otherbodily fluid of an animal.

Therapeutic Formulations and Modes of Administration

The present disclosure features methods for treating conditions orpreventing pre-conditions which respond to an inhibition of PD-L1biological activity. Preferred examples are conditions that arecharacterized by inflammation or cellular hyperproliferation. Techniquesand dosages for administration vary depending on the type of specificpolypeptide and the specific condition being treated but can be readilydetermined by the skilled artisan. In general, regulatory agenciesrequire that a protein reagent to be used as a therapeutic is formulatedso as to have acceptably low levels of pyrogens. Accordingly,therapeutic formulations will generally be distinguished from otherformulations in that they are substantially pyrogen free, or at leastcontain no more than acceptable levels of pyrogen as determined by theappropriate regulatory agency (e.g., FDA).

Therapeutic compositions of the present disclosure may be administeredwith a pharmaceutically acceptable diluent, carrier, or excipient, inunit dosage form. Administration may be parenteral (e.g., intravenous,subcutaneous), oral, or topical, as non-limiting examples. In addition,any gene therapy technique, using nucleic acids encoding thepolypeptides of the invention, may be employed, such as naked DNAdelivery, recombinant genes and vectors, cell-based delivery, includingex vivo manipulation of patients' cells, and the like.

The composition can be in the form of a pill, tablet, capsule, liquid,or sustained release tablet for oral administration; or a liquid forintravenous, subcutaneous or parenteral administration; gel, lotion,ointment, cream, or a polymer or other sustained release vehicle forlocal administration.

Methods well known in the art for making formulations are found, forexample, in “Remington: The Science and Practice of Pharmacy” (20th ed.,ed. A. R. Gennaro A R., 2000, Lippincott Williams & Wilkins,Philadelphia, Pa.). Formulations for parenteral administration may, forexample, contain excipients, sterile water, saline, polyalkylene glycolssuch as polyethylene glycol, oils of vegetable origin, or hydrogenatednapthalenes. Biocompatible, biodegradable lactide polymer,lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylenecopolymers may be used to control the release of the compounds.Nanoparticulate formulations (e.g., biodegradable nanoparticles, solidlipid nanoparticles, liposomes) may be used to control thebiodistribution of the compounds. Other potentially useful parenteraldelivery systems include ethylene-vinyl acetate copolymer particles,osmotic pumps, implantable infusion systems, and liposomes. Theconcentration of the compound in the formulation varies depending upon anumber of factors, including the dosage of the drug to be administered,and the route of administration.

The polypeptide may be optionally administered as a pharmaceuticallyacceptable salt, such as non-toxic acid addition salts or metalcomplexes that are commonly used in the pharmaceutical industry.Examples of acid addition salts include organic acids such as acetic,lactic, pamoic, maleic, citric, malic, ascorbic, succinic, benzoic,palmitic, suberic, salicylic, tartaric, methanesulfonic,toluenesulfonic, or trifluoroacetic acids or the like; polymeric acidssuch as tannic acid, carboxymethyl cellulose, or the like; and inorganicacid such as hydrochloric acid, hydrobromic acid, sulfuric acidphosphoric acid, or the like. Metal complexes include zinc, iron, andthe like. In one example, the polypeptide is formulated in the presenceof sodium acetate to increase thermal stability.

Formulations for oral use include tablets containing the activeingredient(s) in a mixture with non-toxic pharmaceutically acceptableexcipients. These excipients may be, for example, inert diluents orfillers (e.g., sucrose and sorbitol), lubricating agents, glidants, andanti-adhesives (e.g., magnesium stearate, zinc stearate, stearic acid,silicas, hydrogenated vegetable oils, or talc).

Formulations for oral use may also be provided as chewable tablets, oras hard gelatin capsules wherein the active ingredient is mixed with aninert solid diluent, or as soft gelatin capsules wherein the activeingredient is mixed with water or an oil medium.

A therapeutically effective dose refers to a dose that produces thetherapeutic effects for which it is administered. The exact dose willdepend on the disorder to be treated, and may be ascertained by oneskilled in the art using known techniques. In general, the polypeptideis administered at about 0.01 μg/kg to about 50 mg/kg per day,preferably 0.01 mg/kg to about 30 mg/kg per day, most preferably 0.1mg/kg to about 20 mg/kg per day. The polypeptide may be given daily(e.g., once, twice, three times, or four times daily) or preferably lessfrequently (e.g., weekly, every two weeks, every three weeks, monthly,or quarterly). In addition, as is known in the art, adjustments for ageas well as the body weight, general health, sex, diet, time ofadministration, drug interaction, and the severity of the disease may benecessary, and will be ascertainable with routine experimentation bythose skilled in the art.

Pharmaceutical Formulations of Disclosed Antibodies with Tumor Vaccines

A combined therapeutic product or formulation of a disclosed anti-PD-L1antibody with a therapeutic vaccine provides synergistic oncologictherapeutic benefit. For example, the present disclosure provides acombination of a disclosed anti-PD-L1 antibody with “Neuvax” which is aE75-derived 9 mer synthetic peptide isolated from HER2/neu combined withGM-CSF as an adjuvant as described in U.S. Pat. No. 8,222,214, thedisclosure of which is incorporated by reference herein. In addition,the present disclosure provides a combination of a disclosed anti-PD-L1antibody with ALVAC-CEA vaccine, which is a canary pox virus combinedwith carcinoembryonic antigen.

Exemplary Uses

The PD-L1 binding proteins described herein and their related variantsare useful in a number of therapeutic and diagnostic applications. Theseinclude the inhibition of the biological activity of PD-L1 by competingfor or blocking the binding to a PD-L1 as well as the delivery ofcytotoxic or imaging moieties to cells, preferably cells expressingPD-L1. The small size and stable structure of these molecules can beparticularly valuable with respect to manufacturing of the drug, rapidclearance from the body for certain applications where rapid clearanceis desired or formulation into novel delivery systems that are suitableor improved using a molecule with such characteristics.

On the basis of their efficacy as inhibitors of PD-L1 biologicalactivity, the polypeptides of this disclosure are effective against anumber of cancer conditions as well as complications arising fromcancer, such as pleural effusion and ascites. Preferably, thePD-L1-binding polypeptides of the disclosure can be used for thetreatment of prevention of hyperproliferative diseases or cancer and themetastatic spread of cancers. Preferred indications for the disclosedanti-PD-L1 antibodies include colorectal cancers, head and neck cancers,small cell lung cancer, non-small cell lung cancer (NSCLC) andpancreatic cancer. Non-limiting examples of cancers include bladder,blood, bone, brain, breast, cartilage, colon kidney, liver, lung, lymphnode, nervous tissue, ovary, pancreatic, prostate, skeletal muscle,skin, spinal cord, spleen, stomach, testes, thymus, thyroid, trachea,urogenital tract, ureter, urethra, uterus, or vaginal cancer.

In addition, various inflammatory disorders can be treated with thedisclosed anti-PD-L1 binding polypeptides disclosed herein. Suchinflammatory disorders include, for example, intestinal mucosainflammation wasting diseases associated with colitis, multiplesclerosis, systemic lupus erythematosus, viral infections, rheumatoidarthritis, osteoarthritis, psoriasis, and Crohn's disease.

A PD-L1 binding polypeptide can be administered alone or in combinationwith one or more additional therapies such as chemotherapy radiotherapy,immunotherapy, surgical intervention, or any combination of these.Long-term therapy is equally possible as is adjuvant therapy in thecontext of other treatment strategies, as described above.

In certain embodiments of such methods, one or more polypeptidetherapeutic agents can be administered, together (simultaneously) or atdifferent times (sequentially). In addition, polypeptide therapeuticagents can be administered with another type of compounds for treatingcancer or for inhibiting angiogenesis.

In certain embodiments, the subject anti-PD-L1 antibodies agents of theinvention can be used alone. Alternatively, the subject agents may beused in combination with other conventional anti-cancer therapeuticapproaches directed to treatment or prevention of proliferativedisorders (e.g., tumor). For example, such methods can be used inprophylactic cancer prevention, prevention of cancer recurrence andmetastases after surgery, and as an adjuvant of other conventionalcancer therapy. The present disclosure recognizes that the effectivenessof conventional cancer therapies (e.g., chemotherapy, radiation therapy,phototherapy, immunotherapy, and surgery) can be enhanced through theuse of a subject polypeptide therapeutic agent.

A wide array of conventional compounds have been shown to haveanti-neoplastic activities. These compounds have been used aspharmaceutical agents in chemotherapy to shrink solid tumors, preventmetastases and further growth, or decrease the number of malignant cellsin leukemic or bone marrow malignancies. Although chemotherapy has beeneffective in treating various types of malignancies, manyanti-neoplastic compounds induce undesirable side effects. It has beenshown that when two or more different treatments are combined, thetreatments may work synergistically and allow reduction of dosage ofeach of the treatments, thereby reducing the detrimental side effectsexerted by each compound at higher dosages. In other instances,malignancies that are refractory to a treatment may respond to acombination therapy of two or more different treatments.

When a polypeptide therapeutic agent of the present invention isadministered in combination with another conventional anti-neoplasticagent, either concomitantly or sequentially, such therapeutic agent maybe found to enhance the therapeutic effect of the anti-neoplastic agentor overcome cellular resistance to such anti-neoplastic agent. Thisallows decrease of dosage of an anti-neoplastic agent, thereby reducingthe undesirable side effects, or restores the effectiveness of ananti-neoplastic agent in resistant cells.

Pharmaceutical compounds that may be used for combinatory anti-tumortherapy include, merely to illustrate: aminoglutethimide, amsacrine,anastrozole, asparaginase, bcg, bicalutamide, bleomycin, buserelin,busulfan, campothecin, capecitabine, carboplatin, carmustine,chlorambucil, cisplatin, cladribine, clodronate, colchicine,cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin,daunorubicin, dienestrol, diethylstilbestrol, docetaxel, doxorubicin,epirubicin, estradiol, estramustine, etoposide, exemestane, filgrastim,fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide,gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide,imatinib, interferon, irinotecan, ironotecan, letrozole, leucovorin,leuprolide, levamisole, lomustine, mechlorethamine, medroxyprogesterone,megestrol, melphalan, mercaptopurine, mesna, methotrexate, mitomycin,mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, oxaliplatin,paclitaxel, pamidronate, pentostatin, plicamycin, porfimer,procarbazine, raltitrexed, rituximab, streptozocin, suramin, tamoxifen,temozolomide, teniposide, testosterone, thioguanine, thiotepa,titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine,vincristine, vindesine, and vinorelbine.

Certain chemotherapeutic anti-tumor compounds may be categorized bytheir mechanism of action into, for example, following groups:anti-metabolites/anti-cancer agents, such as pyrimidine analogs(5-fluorouracil, floxuridine, capecitabine, gemcitabine and cytarabine)and purine analogs, folate antagonists and related inhibitors(mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine(cladribine)); antiproliferative/antimitotic agents including naturalproducts such as vinca alkaloids (vinblastine, vincristine, andvinorelbine), microtubule disruptors such as taxane (paclitaxel,docetaxel), vincristin, vinblastin, nocodazole, epothilones andnavelbine, epidipodophyllotoxins (etoposide, teniposide), DNA damagingagents (actinomycin, amsacrine, anthracyclines, bleomycin, busulfan,camptothecin, carboplatin, chlorambucil, cisplatin, cyclophosphamide,cytoxan, dactinomycin, daunorubicin, doxorubicin, epirubicin,hexamethylmelamineoxaliplatin, iphosphamide, melphalan,merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, plicamycin,procarbazine, taxol, taxotere, teniposide, triethylenethiophosphoramideand etoposide (VP16)); antibiotics such as dactinomycin (actinomycin D),daunorubicin, doxorubicin (adriamycin), idarubicin, anthracyclines,mitoxantrone, bleomycins, plicamycin (mithramycin) and mitomycin;enzymes (L-asparaginase which systemically metabolizes L-asparagine anddeprives cells which do not have the capacity to synthesize their ownasparagine); antiplatelet agents; antiproliferative/antimitoticalkylating agents such as nitrogen mustards (mechlorethamine,cyclophosphamide and analogs, melphalan, chlorambucil), ethyleniminesand methylmelamines (hexamethylmelamine and thiotepa), alkylsulfonates-busulfan, nitrosoureas (carmustine (BCNU) and analogs,streptozocin), trazenes—dacarbazinine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate); platinum coordination complexes (cisplatin,carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide;hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide,nilutamide) and aromatase inhibitors (letrozole, anastrozole);anticoagulants (heparin, synthetic heparin salts and other inhibitors ofthrombin); fibrinolytic agents (such as tissue plasminogen activator,streptokinase and urokinase), aspirin, dipyridamole, ticlopidine,clopidogrel, abciximab; antimigratory agents; antisecretory agents(breveldin); immunosuppressives (cyclosporine, tacrolimus (FK-506),sirolimus (rapamycin), azathioprine, mycophenolate mofetil);anti-angiogenic compounds (TNP-470, genistein) and growth factorinhibitors (e.g., VEGF inhibitors, fibroblast growth factor (FGF)inhibitors); angiotensin receptor blocker; nitric oxide donors;anti-sense oligonucleotides; antibodies (trastuzumab); cell cycleinhibitors and differentiation inducers (tretinoin); mTOR inhibitors,topoisomerase inhibitors (doxorubicin (adriamycin), amsacrine,camptothecin, daunorubicin, dactinomycin, eniposide, epirubicin,etoposide, idarubicin and mitoxantrone, topotecan, irinotecan),corticosteroids (cortisone, dexamethasone, hydrocortisone,methylpednisolone, prednisone, and prenisolone); growth factor signaltransduction kinase inhibitors; mitochondrial dysfunction inducers andcaspase activators; and chromatin disruptors.

Depending on the nature of the combinatory therapy, administration ofthe polypeptide therapeutic agents may be continued while the othertherapy is being administered and/or thereafter. Administration of thepolypeptide therapeutic agents may be made in a single dose, or inmultiple doses. In some instances, administration of the polypeptidetherapeutic agents is commenced at least several days prior to theconventional therapy, while in other instances, administration is beguneither immediately before or at the time of the administration of theconventional therapy.

In one example of a diagnostic application, a biological sample, such asserum or a tissue biopsy, from a patient suspected of having a conditioncharacterized by inappropriate angiogenesis is contacted with adetectably labeled polypeptide of the disclosure to detect levels ofPD-L1. The levels of PD-L1 detected are then compared to levels of PD-L1detected in a normal sample also contacted with the labeled polypeptide.An increase of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%in the levels of the PD-L1 may be considered a diagnostic indicator.

In certain embodiments, the PD-L1 binding polypeptides are furtherattached to a label that is able to be detected (e.g., the label can bea radioisotope, fluorescent compound, enzyme or enzyme co-factor). Theactive moiety may be a radioactive agent, such as: radioactive heavymetals such as iron chelates, radioactive chelates of gadolinium ormanganese, positron emitters of oxygen, nitrogen, iron, carbon, orgallium, ⁴³K, ⁵²Fe, ⁵⁷Co, ⁶⁷Cu, ⁶⁷Ga, ⁶⁸Ga, ¹²³I, ¹²⁵I, ¹³¹I, ¹³²I, or⁹⁹Tc. A binding agent affixed to such a moiety may be used as an imagingagent and is administered in an amount effective for diagnostic use in amammal such as a human and the localization and accumulation of theimaging agent is then detected. The localization and accumulation of theimaging agent may be detected by radioscintigraphy, nuclear magneticresonance imaging, computed tomography or positron emission tomography.Immunoscintigraphy using PD-L1 binding polypeptides directed at PD-L1may be used to detect and/or diagnose cancers and vasculature. Forexample, any of the binding polypeptide against a PD-L1 marker labeledwith ⁹⁹Technetium, ¹¹¹Indium, or ¹²⁵Iodine may be effectively used forsuch imaging. As will be evident to the skilled artisan, the amount ofradioisotope to be administered is dependent upon the radioisotope.Those having ordinary skill in the art can readily formulate the amountof the imaging agent to be administered based upon the specific activityand energy of a given radionuclide used as the active moiety. Typically0.1-100 millicuries per dose of imaging agent, preferably 1-10millicuries, most often 2-5 millicuries are administered. Thus,compositions according to the present invention useful as imaging agentscomprising a targeting moiety conjugated to a radioactive moietycomprise 0.1-100 millicuries, in some embodiments preferably 1-10millicuries, in some embodiments preferably 2-5 millicuries, in someembodiments more preferably 1-5 millicuries.

The PD-L1 binding polypeptides can also be used to deliver additionaltherapeutic agents (including but not limited to drug compounds,chemotherapeutic compounds, and radiotherapeutic compounds) to a cell ortissue expressing PD-L1. In one example, the PD-L1 binding polypeptideis fused to a chemotherapeutic agent for targeted delivery of thechemotherapeutic agent to a tumor cell or tissue expressing PD-L1.

The PD-L1 binding polypeptides are useful in a variety of applications,including research, diagnostic and therapeutic applications. Forinstance, they can be used to isolate and/or purify receptor or portionsthereof, and to study receptor structure (e.g., conformation) andfunction.

In certain aspects, the various binding polypeptides can be used todetect or measure the expression of PD-L1, for example, on endothelialcells (e.g., venous endothelial cells), or on cells transfected with aPD-L1 gene. Thus, they also have utility in applications such as cellsorting and imaging (e.g., flow cytometry, and fluorescence activatedcell sorting), for diagnostic or research purposes.

In certain embodiments, the binding polypeptides of fragments thereofcan be labeled or unlabeled for diagnostic purposes. Typically,diagnostic assays entail detecting the formation of a complex resultingfrom the binding of a binding polypeptide to PD-L1. The bindingpolypeptides or fragments can be directly labeled, similar toantibodies. A variety of labels can be employed, including, but notlimited to, radionuclides, fluorescers, enzymes, enzyme substrates,enzyme cofactors, enzyme inhibitors and ligands (e.g., biotin, haptens).Numerous appropriate immunoassays are known to the skilled artisan (U.S.Pat. Nos. 3,817,827; 3,850,752; 3,901,654; and 4,098,876). Whenunlabeled, the binding polypeptides can be used in assays, such asagglutination assays. Unlabeled binding polypeptides can also be used incombination with another (one or more) suitable reagent which can beused to detect the binding polypeptide, such as a labeled antibodyreactive with the binding polypeptide or other suitable reagent (e.g.,labeled protein A).

In one embodiment, the binding polypeptides of the present invention canbe utilized in enzyme immunoassays, wherein the subject polypeptides areconjugated to an enzyme. When a biological sample comprising a PD-L1protein is combined with the subject binding polypeptides, bindingoccurs between the binding polypeptides and the PD-L1 protein. In oneembodiment, a sample containing cells expressing a PD-L1 protein (e.g.,endothelial cells) is combined with the subject antibodies, and bindingoccurs between the binding polypeptides and cells bearing a PD-L1protein recognized by the binding polypeptide. These bound cells can beseparated from unbound reagents and the presence of the bindingpolypeptide-enzyme conjugate specifically bound to the cells can bedetermined, for example, by contacting the sample with a substrate ofthe enzyme which produces a color or other detectable change when actedon by the enzyme. In another embodiment, the subject bindingpolypeptides can be unlabeled, and a second, labeled polypeptide (e.g.,an antibody) can be added which recognizes the subject bindingpolypeptide.

In certain aspects, kits for use in detecting the presence of a PD-L1protein in a biological sample can also be prepared. Such kits willinclude a PD-L1 binding polypeptide which binds to a PD-L1 protein orportion of said receptor, as well as one or more ancillary reagentssuitable for detecting the presence of a complex between the bindingpolypeptide and the receptor protein or portions thereof. Thepolypeptide compositions of the present invention can be provided inlyophilized form, either alone or in combination with additionalantibodies specific for other epitopes. The binding polypeptides and/orantibodies, which can be labeled or unlabeled, can be included in thekits with adjunct ingredients (e.g., buffers, such as Tris, phosphateand carbonate, stabilizers, excipients, biocides and/or inert proteins,e.g., bovine serum albumin). For example, the binding polypeptidesand/or antibodies can be provided as a lyophilized mixture with theadjunct ingredients, or the adjunct ingredients can be separatelyprovided for combination by the user. Generally these adjunct materialswill be present in less than about 5% weight based on the amount ofactive binding polypeptide or antibody, and usually will be present in atotal amount of at least about 0.001% weight based on polypeptide orantibody concentration. Where a second antibody capable of binding tothe binding polypeptide is employed, such antibody can be provided inthe kit, for instance in a separate vial or container. The secondantibody, if present, is typically labeled, and can be formulated in ananalogous manner with the antibody formulations described above.

Similarly, the present disclosure also provides a method of detectingand/or quantitating expression of PD-L1, wherein a compositioncomprising a cell or fraction thereof (e.g., membrane fraction) iscontacted with a binding polypeptide which binds to a PD-L1 or portionof the receptor under conditions appropriate for binding thereto, andthe binding is monitored. Detection of the binding polypeptide,indicative of the formation of a complex between binding polypeptide andPD-L1 or a portion thereof, indicates the presence of the receptor.Binding of a polypeptide to the cell can be determined by standardmethods, such as those described in the working examples. The method canbe used to detect expression of PD-L1 on cells from an individual.Optionally, a quantitative expression of PD-L1 on the surface ofendothelial cells can be evaluated, for instance, by flow cytometry, andthe staining intensity can be correlated with disease susceptibility,progression or risk.

The present disclosure also provides a method of detecting thesusceptibility of a mammal to certain diseases. To illustrate, themethod can be used to detect the susceptibility of a mammal to diseaseswhich progress based on the amount of PD-L1 present on cells and/or thenumber of PD-L1-positive cells in a mammal.

Polypeptide sequences are indicated using standard one- or three-letterabbreviations. Unless otherwise indicated, each polypeptide sequence hasamino termini at the left and a carboxy termini at the right; eachsingle-stranded nucleic acid sequence, and the top strand of eachdouble-stranded nucleic acid sequence, has a 5′ termini at the left anda 3′ termini at the right. A particular polypeptide sequence also can bedescribed by explaining how it differs from a reference sequence.

The terms “PD-L1 inhibitor” and “PD-L1 antagonist” are usedinterchangeably. Each is a molecule that detectably inhibits at leastone function of PD-L1. Conversely, a “PD-L1 agonist” is a molecule thatdetectably increases at least one function of PD-L1. The inhibitioncaused by a PD-L1 inhibitor need not be complete so long as it isdetectable using an assay. Any assay of a function of PD-L1 can be used,examples of which are provided herein. Examples of functions of PD-L1that can be inhibited by a PD-L1 inhibitor, or increased by a PD-L1agonist, include cancer cell growth or apoptosis (programmed celldeath), and so on. Examples of types of PD-L1 inhibitors and PD-L1agonists include, but are not limited to, PD-L1 binding polypeptidessuch as antigen binding proteins (e.g., PD-L1 inhibiting antigen bindingproteins), antibodies, antibody fragments, and antibody derivatives.

The terms “peptide,” “polypeptide” and “protein” each refers to amolecule comprising two or more amino acid residues joined to each otherby peptide bonds. These terms encompass, e.g., native and artificialproteins, protein fragments and polypeptide analogs (such as muteins,variants, and fusion proteins) of a protein sequence as well aspost-translationally, or otherwise covalently or non-covalently,modified proteins. A peptide, polypeptide, or protein may be monomericor polymeric.

A “variant” of a polypeptide (for example, an antibody) comprises anamino acid sequence wherein one or more amino acid residues are insertedinto, deleted from and/or substituted into the amino acid sequencerelative to another polypeptide sequence. Disclosed variants include,for example, fusion proteins.

A “derivative” of a polypeptide is a polypeptide (e.g., an antibody)that has been chemically modified, e.g., via conjugation to anotherchemical moiety (such as, for example, polyethylene glycol or albumin,e.g., human serum albumin), phosphorylation, and glycosylation. Unlessotherwise indicated, the term “antibody” includes, in addition toantibodies comprising two full-length heavy chains and two full-lengthlight chains, derivatives, variants, fragments, and muteins thereof,examples of which are described below.

An “antigen binding protein” is a protein comprising a portion thatbinds to an antigen and, optionally, a scaffold or framework portionthat allows the antigen binding portion to adopt a conformation thatpromotes binding of the antigen binding protein to the antigen. Examplesof antigen binding proteins include antibodies, antibody fragments(e.g., an antigen binding portion of an antibody), antibody derivatives,and antibody analogs. The antigen binding protein can comprise, forexample, an alternative protein scaffold or artificial scaffold withgrafted CDRs or CDR derivatives. Such scaffolds include, but are notlimited to, antibody-derived scaffolds comprising mutations introducedto, for example, stabilize the three-dimensional structure of theantigen binding protein as well as wholly synthetic scaffoldscomprising, for example, a biocompatible polymer. See, for example,Korndorfer et al., 2003, Proteins: Structure, Function, andBioinformatics, Volume 53, Issue 1:121-129; Roque et al., 2004,Biotechnol. Prog. 20:639-654. In addition, peptide antibody mimetics(“PAMs”) can be used, as well as scaffolds based on antibody mimeticsutilizing fibronection components as a scaffold.

An antigen binding protein can have, for example, the structure of anaturally occurring immunoglobulin. An “immunoglobulin” is a tetramericmolecule. In a naturally occurring immunoglobulin, each tetramer iscomposed of two identical pairs of polypeptide chains, each pair havingone “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa). Theamino-terminal portion of each chain includes a variable region of about100 to 110 or more amino acids primarily responsible for antigenrecognition. The carboxy-terminal portion of each chain defines aconstant region primarily responsible for effector function. Human lightchains are classified as kappa or lambda light chains. Heavy chains areclassified as mu, delta, gamma, alpha, or epsilon, and define theantibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.Preferably, the anti-PD-L1 antibodies disclosed herein are characterizedby their variable domain region sequences in the heavy V_(H) and lightV_(L) amino acid sequences. The preferred antibody is A6 which is akappa IgG antibody. Within light and heavy chains, the variable andconstant regions are joined by a “J” region of about 12 or more aminoacids, with the heavy chain also including a “D” region of about 10 moreamino acids. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed.,2nd ed. Raven Press, N.Y. (1989)). The variable regions of eachlight/heavy chain pair form the antibody binding site such that anintact immunoglobulin has two binding sites.

A “multi-specific antibody” is an antibody that recognizes more than oneepitope on one or more antigens. A subclass of this type of antibody isa “bi-specific antibody” which recognizes two distinct epitopes on thesame or different antigens.

An antigen binding protein “specifically binds” to an antigen (e.g.,human PD-L1) if it binds to the antigen with a dissociation constant of1 nanomolar or less.

An “antigen binding domain, “antigen binding region,” or “antigenbinding site” is a portion of an antigen binding protein that containsamino acid residues (or other moieties) that interact with an antigenand contribute to the antigen binding protein's specificity and affinityfor the antigen. For an antibody that specifically binds to its antigen,this will include at least part of at least one of its CDR domains.

An “epitope” is the portion of a molecule that is bound by an antigenbinding protein (e.g., by an antibody). An epitope can comprisenon-contiguous portions of the molecule (e.g., in a polypeptide, aminoacid residues that are not contiguous in the polypeptide's primarysequence but that, in the context of the polypeptide's tertiary andquaternary structure, are near enough to each other to be bound by anantigen binding protein).

The “percent homology” of two polynucleotide or two polypeptidesequences is determined by comparing the sequences using the GAPcomputer program (a part of the GCG Wisconsin Package, version 10.3(Accelrys, San Diego, Calif.)) using its default parameters.

A “host cell” is a cell that can be used to express a nucleic acid. Ahost cell can be a prokaryote, for example, E. coli, or it can be aeukaryote, for example, a single-celled eukaryote (e.g., a yeast orother fungus), a plant cell (e.g., a tobacco or tomato plant cell), ananimal cell (e.g., a human cell, a monkey cell, a hamster cell, a ratcell, a mouse cell, or an insect cell) or a hybridoma. Examples of hostcells include the COS-7 line of monkey kidney cells (ATCC CRL 1651)(Gluzman et al., 1981, Cell 23:175), L cells, C127 cells, 3T3 cells(ATCC CCL 163), Chinese hamster ovary (CHO) cells or their derivativessuch as Veggie CHO and related cell lines which grow in serum-free media(Rasmussen et al., 1998, Cytotechnology 28:31) or CHO strain DX-B11,which is deficient in DHFR (Urlaub et al., 1980, Proc. Natl. Acad. Sci.USA 77:4216-20), HeLa cells, BHK (ATCC CRL 10) cell lines, the CV1/EBNAcell line derived from the African green monkey kidney cell line CV1(ATCC CCL 70) (McMahan et al., 1991, EMBO J. 10:2821), human embryonickidney cells such as 293,293 EBNA or MSR 293, human epidermal A431cells, human Colo205 cells, other transformed primate cell lines, normaldiploid cells, cell strains derived from in vitro culture of primarytissue, primary explants, HL-60, U937, HaK or Jurkat cells. Typically, ahost cell is a cultured cell that can be transformed or transfected witha polypeptide-encoding nucleic acid, which can then be expressed in thehost cell. The phrase “recombinant host cell” can be used to denote ahost cell that has been transformed or transfected with a nucleic acidto be expressed. A host cell also can be a cell that comprises thenucleic acid but does not express it at a desired level unless aregulatory sequence is introduced into the host cell such that itbecomes operably linked with the nucleic acid. It is understood that theterm host cell refers not only to the particular subject cell but alsoto the progeny or potential progeny of such a cell. Because certainmodifications may occur in succeeding generations due to, e.g., mutationor environmental influence, such progeny may not, in fact, be identicalto the parent cell, but are still included within the scope of the termas used herein.

Antigen Binding Proteins

Antigen binding proteins (e.g., antibodies, antibody fragments, antibodyderivatives, antibody muteins, and antibody variants) are polypeptidesthat bind to PD-L1, (preferably, human PD-L1). Antigen binding proteinsinclude antigen binding proteins that inhibit a biological activity ofPD-L1.

Oligomers that contain one or more antigen binding proteins may beemployed as PD-L1 antagonists. Oligomers may be in the form ofcovalently-linked or non-covalently-linked dimers, trimers, or higheroligomers. Oligomers comprising two or more antigen binding protein arecontemplated for use, with one example being a homodimer. Otheroligomers include heterodimers, homotrimers, heterotrimers,homotetramers, heterotetramers, etc.

One embodiment is directed to oligomers comprising multiple antigenbinding proteins joined via covalent or non-covalent interactionsbetween peptide moieties fused to the antigen binding proteins. Suchpeptides may be peptide linkers (spacers), or peptides that have theproperty of promoting oligomerization. Leucine zippers and certainpolypeptides derived from antibodies are among the peptides that canpromote oligomerization of antigen binding proteins attached thereto, asdescribed in more detail below.

In particular embodiments, the oligomers comprise from two to fourantigen binding proteins. The antigen binding proteins of the oligomermay be in any form, such as any of the forms described above, e.g.,variants or fragments. Preferably, the oligomers comprise antigenbinding proteins that have PD-L1 binding activity.

In one embodiment, an oligomer is prepared using polypeptides derivedfrom immunoglobulins. Preparation of Fusion Proteins Comprising CertainHeterologous Polypeptides Fused to Various Portions of antibody-derivedpolypeptides (including the Fc domain) has been described, e.g., byAshkenazi et al., 1991, Proc. Natl. Acad. Sci. USA 88:10535; Byrn etal., 1990, Nature 344:677; and Hollenbaugh et al., 1992 “Construction ofImmunoglobulin Fusion Proteins”, in Current Protocols in Immunology,Suppl. 4, pages 10.19.1-10.19.11.

One embodiment is directed to a dimer comprising two fusion proteinscreated by fusing a PD-L1 binding fragment of an anti-PD-L1 antibody tothe Fc region of an antibody. The dimer can be made by, for example,inserting a gene fusion encoding the fusion protein into an appropriateexpression vector, expressing the gene fusion in host cells transformedwith the recombinant expression vector, and allowing the expressedfusion protein to assemble much like antibody molecules, whereuponinterchain disulfide bonds form between the Fc moieties to yield thedimer.

The term “Fc polypeptide” includes native and mutein forms ofpolypeptides derived from the Fc region of an antibody. Truncated formsof such polypeptides containing the hinge region that promotesdimerization also are included. Fusion proteins comprising Fc moieties(and oligomers formed therefrom) offer the advantage of facilepurification by affinity chromatography over Protein A or Protein Gcolumns.

Another method for preparing oligomeric antigen binding proteinsinvolves use of a leucine zipper. Leucine zipper domains are peptidesthat promote oligomerization of the proteins in which they are found.Leucine zippers were originally identified in several DNA-bindingproteins (Landschulz et al., 1988, Science 240:1759), and have sincebeen found in a variety of different proteins. Among the known leucinezippers are naturally occurring peptides and derivatives thereof thatdimerize or trimerize. Examples of leucine zipper domains suitable forproducing soluble oligomeric proteins are described in WO 94/10308, andthe leucine zipper derived from lung surfactant protein D (SPD)described in Hoppe et al., 1994, FEBS Letters 344:191. The use of amodified leucine zipper that allows for stable trimerization of aheterologous protein fused thereto is described in Fanslow et al., 1994,Semin. Immunol. 6:267-78. In one approach, recombinant fusion proteinscomprising an anti-PD-L1 antibody fragment or derivative fused to aleucine zipper peptide are expressed in suitable host cells, and thesoluble oligomeric anti-PD-L1 antibody fragments or derivatives thatform are recovered from the culture supernatant.

Antigen-binding fragments of antigen binding proteins of the inventionmay be produced by conventional techniques. Examples of such fragmentsinclude, but are not limited to, Fab and F(ab′)₂ fragments.

The present disclosure provides monoclonal antibodies that bind toPD-L1. Monoclonal antibodies may be produced using any technique knownin the art, e.g., by immortalizing spleen cells harvested from thetransgenic animal after completion of the immunization schedule. Thespleen cells can be immortalized using any technique known in the art,e.g., by fusing them with myeloma cells to produce hybridomas. Myelomacells for use in hybridoma-producing fusion procedures preferably arenon-antibody-producing, have high fusion efficiency, and enzymedeficiencies that render them incapable of growing in certain selectivemedia which support the growth of only the desired fused cells(hybridomas). Examples of suitable cell lines for use in mouse fusionsinclude Sp-20, P3-X63/Ag8, P3-X63-Ag8.653, NS1/1.Ag 41, Sp210-Ag14, FO,NSO/U, MPC-11, MPC11-X45-GTG 1.7 and S194/5XX0 Bul; examples of celllines used in rat fusions include R210.RCY3, Y3-Ag 1.2.3, IR983F and48210. Other cell lines useful for cell fusions are U-266, GM1500-GRG2,LICR-LON-HMy2 and UC729-6.

Antigen binding proteins directed against PD-L1 can be used, forexample, in assays to detect the presence of PD-L1 polypeptides, eitherin vitro or in vivo. The antigen binding proteins also may be employedin purifying PD-L1 proteins by immunoaffinity chromatography. Blockingantigen binding proteins can be used in the methods disclosed herein.Such antigen binding proteins that function as PD-L1 antagonists may beemployed in treating any PD-L1-induced condition, including but notlimited to various cancers.

Antigen binding proteins may be employed in an in vitro procedure, oradministered in vivo to inhibit PD-L1-induced biological activity.Disorders caused or exacerbated (directly or indirectly) by theproteolytic activation of PD-L1, examples of which are provided herein,thus may be treated. In one embodiment, the present invention provides atherapeutic method comprising in vivo administration of a PD-L1 blockingantigen binding protein to a mammal in need thereof in an amounteffective for reducing an PD-L1-induced biological activity.

Antigen binding proteins include fully human monoclonal antibodies thatinhibit a biological activity of PD-L1.

Antigen binding proteins may be prepared by any of a number ofconventional techniques. For example, they may be purified from cellsthat naturally express them (e.g., an antibody can be purified from ahybridoma that produces it), or produced in recombinant expressionsystems, using any technique known in the art. See, for example,Monoclonal Antibodies, Hybridomas: A New Dimension in BiologicalAnalyses, Kennet et al. (eds.), Plenum Press, New York (1980); andAntibodies: A Laboratory Manual, Harlow and Land (eds.), Cold SpringHarbor Laboratory Press, Cold Spring Harbor, N.Y., (1988).

Any expression system known in the art can be used to make therecombinant polypeptides of the invention. In general, host cells aretransformed with a recombinant expression vector that comprises DNAencoding a desired polypeptide. Among the host cells that may beemployed are prokaryotes, yeast or higher eukaryotic cells. Prokaryotesinclude gram negative or gram positive organisms, for example E. coli orbacilli. Higher eukaryotic cells include insect cells and establishedcell lines of mammalian origin. Examples of suitable mammalian host celllines include the COS-7 line of monkey kidney cells (ATCC CRL 1651)(Gluzman et al., 1981, Cell 23:175), L cells, 293 cells, C127 cells, 3T3cells (ATCC CCL 163), Chinese hamster ovary (CHO) cells, HeLa cells, BHK(ATCC CRL 10) cell lines, and the CV1/EBNA cell line derived from theAfrican green monkey kidney cell line CV1 (ATCC CCL 70) as described byMcMahan et al., 1991, EMBO J. 10: 2821. Appropriate cloning andexpression vectors for use with bacterial, fungal, yeast, and mammaliancellular hosts are described by Pouwels et al. (Cloning Vectors: ALaboratory Manual, Elsevier, N.Y., 1985).

The transformed cells can be cultured under conditions that promoteexpression of the polypeptide, and the polypeptide recovered byconventional protein purification procedures. One such purificationprocedure includes the use of affinity chromatography, e.g., over amatrix having all or a portion (e.g., the extracellular domain) of PD-L1bound thereto. Polypeptides contemplated for use herein includesubstantially homogeneous recombinant mammalian anti-PD-L1 antibodypolypeptides substantially free of contaminating endogenous materials.

Antigen binding proteins may be prepared, and screened for desiredproperties, by any of a number of known techniques. Certain of thetechniques involve isolating a nucleic acid encoding a polypeptide chain(or portion thereof) of an antigen binding protein of interest (e.g., ananti-PD-L1 antibody), and manipulating the nucleic acid throughrecombinant DNA technology. The nucleic acid may be fused to anothernucleic acid of interest, or altered (e.g., by mutagenesis or otherconventional techniques) to add, delete, or substitute one or more aminoacid residues, for example.

Single chain antibodies may be formed by linking heavy and light chainvariable domain (Fv region) fragments via an amino acid bridge (shortpeptide linker), resulting in a single polypeptide chain. Suchsingle-chain Fvs (scFvs) have been prepared by fusing DNA encoding apeptide linker between DNAs encoding the two variable domainpolypeptides (V_(L) and V_(H)). The resulting polypeptides can fold backon themselves to form antigen-binding monomers, or they can formmultimers (e.g., dimers, trimers, or tetramers), depending on the lengthof a flexible linker between the two variable domains (Kortt et al.,1997, Prot. Eng. 10:423; Kortt et al., 2001, Biomol. Eng. 18:95-108). Bycombining different V_(L) and V_(H)-comprising polypeptides, one canform multimeric scFvs that bind to different epitopes (Kriangkum et al.,2001, Biomol. Eng. 18:31-40). Techniques developed for the production ofsingle chain antibodies include those described in U.S. Pat. No.4,946,778; Bird, 1988, Science 242:423; Huston et al., 1988, Proc. Natl.Acad. Sci. USA 85:5879; Ward et al., 1989, Nature 334:544, de Graaf etal., 2002, Methods Mol. Biol. 178:379-87.

Techniques are known for deriving an antibody of a different subclass orisotype from an antibody of interest, i.e., subclass switching. Thus,IgG antibodies may be derived from an IgM antibody, for example, andvice versa. Such techniques allow the preparation of new antibodies thatpossess the antigen-binding properties of a given antibody (the parentantibody), but also exhibit biological properties associated with anantibody isotype or subclass different from that of the parent antibody.Recombinant DNA techniques may be employed. Cloned DNA encodingparticular antibody polypeptides may be employed in such procedures,e.g., DNA encoding the constant domain of an antibody of the desiredisotype (Lantto et al., 2002, Methods Mol. Biol. 178:303-16). Moreover,if an IgG4 is desired, it may also be desired to introduce a pointmutation (CPSCP→CPPCP) in the hinge region (Bloom et al., 1997, ProteinScience 6:407) to alleviate a tendency to form intra-H chain disulfidebonds that can lead to heterogeneity in the IgG4 antibodies.

In particular embodiments, antigen binding proteins of the presentinvention have a binding affinity (K_(a)) for PD-L1 of at least 10⁶. Inother embodiments, the antigen binding proteins exhibit a K_(a) of atleast 10⁷, at least 10⁸, at least 10⁹, or at least 10¹⁰. In anotherembodiment, the antigen binding protein exhibits a K_(a) substantiallythe same as that of an antibody described herein in the Examples.

In another embodiment, the present disclosure provides an antigenbinding protein that has a low dissociation rate from PD-L1. In oneembodiment, the antigen binding protein has a K_(off) of 1×10⁻⁴ to ⁻¹ orlower. In another embodiment, the K_(off) is 5×10⁻⁵ to ⁻¹ or lower. Inanother embodiment, the K_(off) is substantially the same as an antibodydescribed herein. In another embodiment, the antigen binding proteinbinds to PD-L1 with substantially the same K_(off) as an antibodydescribed herein.

In another aspect, the present disclosure provides an antigen bindingprotein that inhibits an activity of PD-L1. In one embodiment, theantigen binding protein has an IC₅₀ of 1000 nM or lower. In anotherembodiment, the IC₅₀ is 100 nM or lower; in another embodiment, the IC₅₀is 10 nM or lower. In another embodiment, the IC₅₀ is substantially thesame as that of an antibody described herein in the Examples. In anotherembodiment, the antigen binding protein inhibits an activity of PD-L1with substantially the same IC₅₀ as an antibody described herein.

In another aspect, the present disclosure provides an antigen bindingprotein that binds to human PD-L1 expressed on the surface of a celland, when so bound, inhibits PD-L1 signaling activity in the cellwithout causing a significant reduction in the amount of PD-L1 on thesurface of the cell. Any method for determining or estimating the amountof PD-L1 on the surface and/or in the interior of the cell can be used.In other embodiments, binding of the antigen binding protein to thePD-L1-expressing cell causes less than about 75%, 50%, 40%, 30%, 20%,15%, 10%, 5%, 1%, or 0.1% of the cell-surface PD-L1 to be internalized.

In another aspect, the present disclosure provides an antigen bindingprotein having a half-life of at least one day in vitro or in vivo(e.g., when administered to a human subject). In one embodiment, theantigen binding protein has a half-life of at least three days. Inanother embodiment, the antigen binding protein has a half-life of fourdays or longer. In another embodiment, the antigen binding protein has ahalf-life of eight days or longer. In another embodiment, the antigenbinding protein is derivatized or modified such that it has a longerhalf-life as compared to the underivatized or unmodified antigen bindingprotein. In another embodiment, the antigen binding protein contains oneor more point mutations to increase serum half life, such as describedin WO00/09560, incorporated by reference herein.

The present disclosure further provides multi-specific antigen bindingproteins, for example, bispecific antigen binding protein, e.g., antigenbinding protein that bind to two different epitopes of PD-L1, or to anepitope of PD-L1 and an epitope of another molecule, via two differentantigen binding sites or regions. Moreover, bispecific antigen bindingprotein as disclosed herein can comprise a PD-L1 binding site from oneof the herein-described antibodies and a second PD-L1 binding regionfrom another of the herein-described antibodies, including thosedescribed herein by reference to other publications. Alternatively, abispecific antigen binding protein may comprise an antigen binding sitefrom one of the herein described antibodies and a second antigen bindingsite from another PD-L1 antibody that is known in the art, or from anantibody that is prepared by known methods or the methods describedherein.

Numerous methods of preparing bispecific antibodies are known in theart. Such methods include the use of hybrid-hybridomas as described byMilstein et al., 1983, Nature 305:537, and chemical coupling of antibodyfragments (Brennan et al., 1985, Science 229:81; Glennie et al., 1987,J. Immunol. 139:2367; U.S. Pat. No. 6,010,902). Moreover, bispecificantibodies can be produced via recombinant means, for example by usingleucine zipper moieties (i.e., from the Fos and Jun proteins, whichpreferentially form heterodimers; Kostelny et al., 1992, J. Immunol.148:1547) or other lock and key interactive domain structures asdescribed in U.S. Pat. No. 5,582,996. Additional useful techniquesinclude those described in U.S. Pat. Nos. 5,959,083; and 5,807,706.

In another aspect, the antigen binding protein comprises a derivative ofan antibody. The derivatized antibody can comprise any molecule orsubstance that imparts a desired property to the antibody, such asincreased half-life in a particular use. The derivatized antibody cancomprise, for example, a detectable (or labeling) moiety (e.g., aradioactive, colorimetric, antigenic or enzymatic molecule, a detectablebead (such as a magnetic or electrodense (e.g., gold bead), or amolecule that binds to another molecule (e.g., biotin or streptavidin),a therapeutic or diagnostic moiety (e.g., a radioactive, cytotoxic, orpharmaceutically active moiety), or a molecule that increases thesuitability of the antibody for a particular use (e.g., administrationto a subject, such as a human subject, or other in vivo or in vitrouses). Examples of molecules that can be used to derivatize an antibodyinclude albumin (e.g., human serum albumin) and polyethylene glycol(PEG). Albumin-linked and PEGylated derivatives of antibodies can beprepared using techniques well known in the art. In one embodiment, theantibody is conjugated or otherwise linked to transthyretin (TTR) or aTTR variant. The TTR or TTR variant can be chemically modified with, forexample, a chemical selected from the group consisting of dextran,poly(n-vinyl pyurrolidone), polyethylene glycols, propropylene glycolhomopolymers, polypropylene oxide/ethylene oxide co-polymers,polyoxyethylated polyols and polyvinyl alcohols.

Indications

In one aspect, the present disclosure provides methods of treating asubject. The method can, for example, have a generally salubrious effecton the subject, e.g., it can increase the subject's expected longevity.Alternatively, the method can, for example, treat, prevent, cure,relieve, or ameliorate (“treat”) a disease, disorder, condition, orillness (“a condition”). Among the conditions to be treated areconditions characterized by inappropriate expression or activity ofPD-L1. In some such conditions, the expression or activity level is toohigh, and the treatment comprises administering a PD-L1 antagonist asdescribed herein. The disorders or conditions are cancer-related. Inparticular, those cancers include, but are not limited to, lung, ovarianand colon carcinoma and various myelomas.

Specific medical conditions and diseases that are treatable orpreventable with the antigen binding proteins of this disclosure includevarious cancers.

Therapeutic Methods and Administration of Antigen Binding Proteins

Certain methods provided herein comprise administering a PD-L1 bindingantigen binding protein to a subject, thereby reducing a PD-L1-inducedbiological response that plays a role in a particular condition. Inparticular embodiments, methods of the invention involve contactingendogenous PD-L1 with a PD-L1 binding antigen binding protein, e.g., viaadministration to a subject or in an ex vivo procedure.

The term “treatment” encompasses alleviation or prevention of at leastone symptom or other aspect of a disorder, or reduction of diseaseseverity, and the like. An antigen binding protein need not effect acomplete cure, or eradicate every symptom or manifestation of a disease,to constitute a viable therapeutic agent. As is recognized in thepertinent field, drugs employed as therapeutic agents may reduce theseverity of a given disease state, but need not abolish everymanifestation of the disease to be regarded as useful therapeuticagents. Similarly, a prophylactically administered treatment need not becompletely effective in preventing the onset of a condition in order toconstitute a viable prophylactic agent. Simply reducing the impact of adisease (for example, by reducing the number or severity of itssymptoms, or by increasing the effectiveness of another treatment, or byproducing another beneficial effect), or reducing the likelihood thatthe disease will occur or worsen in a subject, is sufficient. Oneembodiment of the invention is directed to a method comprisingadministering to a patient a PD-L1 antagonist in an amount and for atime sufficient to induce a sustained improvement over baseline of anindicator that reflects the severity of the particular disorder.

As is understood in the pertinent field, pharmaceutical compositionscomprising the antibodies and fragments thereof of the disclosure areadministered to a subject in a manner appropriate to the indication.Pharmaceutical compositions may be administered by any suitabletechnique, including but not limited to, parenterally, topically, or byinhalation. If injected, the pharmaceutical composition can beadministered, for example, via intra-articular, intravenous,intramuscular, intralesional, intraperitoneal or subcutaneous routes, bybolus injection, or continuous infusion. Localized administration, e.g.at a site of disease or injury is contemplated, as are transdermaldelivery and sustained release from implants. Delivery by inhalationincludes, for example, nasal or oral inhalation, use of a nebulizer,inhalation of the antagonist in aerosol form, and the like. Otheralternatives include eyedrops; oral preparations including pills,syrups, lozenges or chewing gum; and topical preparations such aslotions, gels, sprays, and ointments.

Use of antigen binding proteins in ex vivo procedures also iscontemplated. For example, a patient's blood or other bodily fluid maybe contacted with an antigen binding protein that binds PD-L1 ex vivo.The antigen binding protein may be bound to a suitable insoluble matrixor solid support material.

Advantageously, antigen binding proteins are administered in the form ofa composition comprising one or more additional components such as aphysiologically acceptable carrier, excipient or diluent. Optionally,the composition additionally comprises one or more physiologicallyactive agents, for example, a second inflammation- or immune-inhibitingsubstance, an anti-angiogenic substance, an analgesic substance, etc.,non-exclusive examples of which are provided herein. In variousparticular embodiments, the composition comprises one, two, three, four,five, or six physiologically active agents in addition to a PD-L1binding antigen binding protein

Combination Therapy

In another aspect, the present disclosure provides a method of treatinga subject with a PD-L1 inhibiting antigen binding protein and one ormore other treatments. In one embodiment, such a combination therapyachieves synergy or an additive effect by, for example, attackingmultiple sites or molecular targets in a tumor. Types of combinationtherapies that can be used in connection with the present inventioninclude inhibiting or activating (as appropriate) multiple nodes in asingle disease-related pathway, multiple pathways in a target cell, andmultiple cell types within a target tissue.

In another embodiment, a combination therapy method comprisesadministering to the subject two, three, four, five, six, or more of thePD-L1 agonists or antagonists described herein. In another embodiment,the method comprises administering to the subject two or more treatmentsthat together inhibit or activate (directly or indirectly)PD-L1-mediated signal transduction. Examples of such methods includeusing combinations of two or more PD-L1 inhibiting antigen bindingproteins, of a PD-L1 inhibiting antigen binding protein and one or moreother therapeutic moiety having anti-cancer properties (for example,cytotoxic agents, and/or immunomodulators), or of a PD-L1 inhibitingantigen binding protein and one or more other treatments (e.g., surgery,or radiation). Furthermore, one or more anti-PD-L1 antibodies orantibody derivatives can be used in combination with one or moremolecules or other treatments, wherein the other molecule(s) and/ortreatment(s) do not directly bind to or affect PD-L1, but whichcombination is effective for treating or preventing the condition beingtreated. In one embodiment, one or more of the molecule(s) and/ortreatment(s) treats or prevents a condition that is caused by one ormore of the other molecule(s) or treatment(s) in the course of therapy,e.g., nausea, fatigue, alopecia, cachexia, insomnia, etc. In every casewhere a combination of molecules and/or other treatments is used, theindividual molecule(s) and/or treatment(s) can be administered in anyorder, over any length of time, which is effective, e.g.,simultaneously, consecutively, or alternately. In one embodiment, themethod of treatment comprises completing a first course of treatmentwith one molecule or other treatment before beginning a second course oftreatment. The length of time between the end of the first course oftreatment and beginning of the second course of treatment can be anylength of time that allows the total course of therapy to be effective,e.g., seconds, minutes, hours, days, weeks, months, or even years.

In another embodiment, the method comprises administering one or more ofthe PD-L1 antagonists described herein and one or more other treatments(e.g., a therapeutic or palliative treatment). Where a method comprisesadministering more than one treatment to a subject, it is to beunderstood that the order, timing, number, concentration, and volume ofthe administrations is limited only by the medical requirements andlimitations of the treatment, i.e., two treatments can be administeredto the subject, e.g., simultaneously, consecutively, alternately, oraccording to any other regimen.

Example 1

This example provides a characterization of the disclosed anti-PD-L1antibodies binding to human PD-L1 expressed on human lymphocytes. Humanperipheral blood mononuclear cells were activated by culture withanti-CD3 for three days to promote expression of PD-L1. Binding wasassessed by adding serial dilutions of the antibody to the activatedlymphocytes. After washing, binding was detected by staining with aphycoerythrin labeled anti-human Ig reagent followed by analysis using aFACS Aria (Becton Dickinson, San Jose, CA). Since the anti-human Igreagent reacts with immunoglobulin on B lymphocytes the cells wereco-staining with an anti-human CD19 APC-Cy5 reagent. Data were obtainedby gating on the CD19 negative lymphocytes and the results are shown inFIG. 1 . Both H6 and H10 antibodies show potent binding activity with anEC₅₀ in the 100 pM range.

Example 2

This example provides the results from binding the disclosed anti-PD-L1antibodies to human lymphocytes. Anti-PD-L1 antibodies were assayed forbinding to non-activated lymphocytes. Peripheral blood mononuclear cellswere incubated with anti-PD-L1 antibodies (1 μg/ml) followed by washing.Binding of the anti-PD-L1 antibody was detected by staining with aphycoerythrin conjugated and human Ig reagent. To identify the stainedpopulations the cells were co-stained with an anti-CD3 FITC or ananti-CD56 APC reagent. Since the anti-human Ig reagent reacts withimmunoglobulin on B lymphocytes the cells were also stained with ananti-human CD19 APC-Cy5 reagent. The data in FIG. 2 were derived fromthe CD19 negative lymphocytes following analysis using a FACSAria(Becton Dickinson, San Jose, CA). The results show that CD56 positive NKcells, but not CD3+ T cells, react with the anti-PD-L1 antibodies.

Example 3

This example provides a showing of the effect of disclosed anti-PD-L1antibodies on lymphocyte proliferation. Anti-PD-L1 antibodies wereassayed for their ability to modulate the response of lymphocytes tostimulation. The anti-PD-L1 antibodies H1, H6 and H10 were added at 10μg/ml to cultures of peripheral blood mononuclear cells labeled with thefluorescent dye carboxyfluorescein (CFSE) and stimulated with anti-CD3(1 ng/ml). After three days of culture, the cells were assayed forproliferative activity by flow cytometry using a FACS Aria (BectonDickinson, San Jose, CA). The results, shown in FIG. 3 , show that theanti-PD-L1 antibodies inhibited lymphocyte proliferation.

Example 4

This example provides a showing of the effect of NK cells on thedisclosed anti-PD-L1 antibodies on mediated inhibition of proliferation.With the anti-PD-L1 antibodies showing a preferential binding to NKcells, the significance of this in the inhibition of proliferation wastested. By cell sorting using a FACS Aria (Becton Dickinson, San Jose,CA) purified population of CD4+, CD8+, CD56+ (NK) and monocytes wereobtained. As a base culture, 1.5×10⁵ CD4+ cells and 3×10⁴ monocytes werestimulated with anti-CD3 (1 ng/ml) with or without H10 anti-PD-L1antibody (10 μg/ml). In separate cultures, either CD8+ cells or NK cells(both at 3×10⁴) were added to this base culture. After three days ofculture, cells were stained for expression of CD25 as a measure oflymphocyte activation as measured by flow cytometry. The results shownin FIG. 4 were compared to those obtained using whole, unfractionatedPBMC (1.5×10⁵). The anti-PD-L1 antibody inhibited the activation oflymphocytes in the cultures containing whole PBMC and those where NKcells were added, but not in the absence of NK cells.

Example 5

This example provides a showing of an effect of anti-PD-L1 on NK cellactivation. Disclosed anti-PD-L1 antibodies were assayed for theirability to promote the activation of lymphocytes. Peripheral bloodmononuclear cells or purified populations of lymphocyte subsets isolatedby cell sorting were cultured with IL-2 (100 U/ml) in the presence orabsence of added anti-PD-L1 antibodies (10 μg/ml). After five days ofculture, cells were stained for expression of CD25 as a measure of cellactivation and analyzed by flow cytometry. The results shown in FIG. 5reveal that H6 and H10 enhance cell activation and that the responsivelymphocyte population is the NK cell.

Example 6

This example provides a showing of an effect of disclosed anti-PD-L1antibodies on the progression of disease in a murine model of multiplesclerosis (MS). Anti-PD-L1 antibodies were assayed for their ability tomodulate the course of disease in mice induced to develop experimentalautoimmune encephalitis (EAE) as a model of MS. Disease was induced inC57Bl/6 mice following injection of myelin oligodendrocyte glycoprotein(MOG) peptide and pertussis toxin. Once symptoms of disease developed,the mice were treated every second day with an intraperitoneal injectionof anti-PD-L1 antibody (0.1 mg). The results shown in FIG. 6 providethat both anti-PD-L1 antibodies H6 and H10 impacted the course ofdisease development with H6 greatly reducing disease severity.

Example 7

This example provides a characterization of the disclosed G12 anti-PD-L1antibody. rhPD-L1 was immobilized on CMS sensor chip using standardNHS/EDC coupling methodology. All measurements were conducted in HBS-EPbuffer with a flow rate of 30 μL/min. Antibody was diluted so as toobtain a series of concentrations. A 1:1 (Langmuir) binding model wasused to fit the data.

Table 1 provides the binding data for G12.

G12 Biacore k_(on) (M⁻¹ s⁻¹) 1.31E+07 k_(off) (s⁻¹) 4.90E−04 Kd (M)3.74E−11

Example 8

This example provides the results from an experiment showing that G12blocks the interaction between rhPD-1 and rhPD-L1. A 96-well ELISA platewas coated with 1 ng/μL PD1/His at 4° C. overnight, then blocked withcasein in PBS. Pre-mixed 20 μl serial 2-fold diluted IgGs (started from20 μg/ml) and 20 μl 0.25 μl/ml PD-L1/Fc and incubated the mixtures 30min. washed the plate with PBS-Tween (PBST) 3 times. Transferred 25 μlthe mixtures to the ELISA plate and incubated 30 min with shaking.Washed 3 times with PBST. Added HRP conjugated Goat anti-human Fc (1:500in casein), used TMB as substrate and developed 30 min. 2M H₂SO₄ wasadded to stop the reaction. Read the OD at 450 nm.

TABLE 2 G12 Blocking PD-1/PD-L1 interaction (M) IC₅₀ 7.288E−11

Example 9

This example illustrates in vitro EC₅₀ data for the binding of G12 tohuman PD-L1 expressed on the surface of CHO cells. This example showsthe binding characteristic for this antibody in terms of the maximalcell binding and the concentration at which 50% binding saturation(EC₅₀) is reached. In this example, the experimental procedure is asfollows: 50,000 CHO-PD-L1 cells were aliquoted into the wells of a96-well, v-bottom plate in 100 μl FACS Buffer (PBS+2% FBS). A dilutioncurve of the antibody was made in FACS Buffer encompassing theconcentrations shown in FIG. 7 . Cells were spun down, washed 1× withFACS Buffer, and then resuspended in 25 μl of antibody solution intriplicate. After 0.5 hr incubation, cells were washed 1× with FACSBuffer and resuspended in 50 μl PE-conjugated, goat anti-human IgG(γ-chain specific) secondary antibody (Southern Biotech Cat #2040-09).Cells were further incubated for 0.5 hr and then washed 1× with FACSBuffer. Cells were resuspended in 25 μl FACS Buffer and the medianfluorescence intensity in the FL2-H channel was determined using theIntellicyt HTFC flow cytometer.

Results: As shown in FIG. 7 and Table 3, the cell binding EC₅₀ for theG12 anti-PD-L1 antibody on CHO-PD-L1 cells was 1.71E-09 M. Data wascollected on the Intellicyt HTFC flow cytometer, processed using FlowJosoftware, and analyzed and plotted in Graph Pad Prizm using non-linearregression fit. Data points are shown as the median fluorescenceintensity (MFI) of positively labeled cells+/−Std Error.

TABLE 3 G12 Cell Binding EC50 (M) CHO-PD-L1 1.71E−09

Example 10

This example provides in vitro IC₅₀ data for the blocking of theinteraction between recombinant human PD-1 (PD-1-Fc Chimera; SinoBiologics) and human PD-L1 expressed CHO cells by anti-PD-L1 antibodyG12. Here, CHO cells expressing PD-L1 were pre-incubated with G12 priorto the addition of rhPD-1-Fc chimeric protein. After incubation andwashing, PD-1 binding to cell surface expressed PD-L1 was detected usingan Alexa-Fluor 647 tagged anti-PD-1 antibody by flow cytometry(Intellicyt HTFC; FL-4H). This example shows that anti-PD-L1 monoclonalantibody G12 was able to inhibit efficiently the binding of PD-1 toPD-L1 expressed on the surface of CHO cells.

Results: As shown in FIG. 8 and Table 4, the IC₅₀ for blocking of thePD-1/PD-L1 cellular interaction by G12 is 1.76E-09 M. Data was collectedon the Intellicyt HTFC flow cytometer, processed using FlowJo software,and analyzed and plotted in Graph Pad Prizm using non-linear regressionfit. Data points are shown as the median fluorescence detected in theFL-4H channel+/−Std Error.

TABLE 4 G12 Inhibition of PD-1/PD-L1 CHO-PD-L1/ 1.76E−09 InteractionIC50 (M) rhPD-1-Fc

Example 11

This example illustrates in vitro EC₅₀ data for the binding of G12 toPD-L1 expressed on the surface of ES-2 human ovarian carcinoma cells.This example shows the binding characteristic for this antibody in termsof the maximal cell binding and the concentration at which 50% bindingsaturation (EC₅₀) is reached. In this example, the experimentalprocedure is as follows: ES-2 cells were treated with 500 IU/ml IFNγ for18 hours to increase PD-L1 levels above basal expression. Afterinduction, 50,000 ES-2 cells were aliquoted into the wells of a 96-well,v-bottom plate in 100 μl FACS Buffer (PBS+2% FBS). A dilution curve ofthe antibody was made in FACS Buffer encompassing the concentrationsshown in FIG. 9 . Cells were spun down, washed 1× with FACS Buffer, andthen resuspended in 25 μl of antibody solution in triplicate. After 0.5hr incubation, cells were washed 1× with FACS Buffer and resuspended in50 μl PE-conjugated, goat anti-human IgG (γ-chain specific) secondaryantibody (Southern Biotech Cat #2040-09). Cells were further incubatedfor 0.5 hr and then washed 1× with FACS Buffer. Cells were resuspendedin 25 μl FACS Buffer and the median fluorescence intensity in the FL2-Hchannel was determined using the Intellicyt HTFC flow cytometer.

Results: As shown in FIG. 9 and Table 5, the cell binding EC₅₀ for theG12 anti-PD-L1 antibody on ES-2 ovarian carcinoma cells was 4.58E-11 M.Data was collected on the Intellicyt HTFC flow cytometer, processedusing FlowJo software, and analyzed and plotted in Graph Pad Prizm usingnon-linear regression fit. Data points are shown as the medianfluorescence detected in the FL-2H channel+/−Std Error. Cell bindingEC₅₀ for anti-PD-L1 mAb G12 against human PD-L1 expressed on ES-2ovarian cancer cells after treatment with 500 IU/ml recombinant hIFNγfor 18 hr is shown in Table 5.

TABLE 5 G12 Cell Binding EC50 (M) ES-2 4.58E−11

Example 12

This example provides a mixed lymphocyte reaction (MLR) to evaluate theeffect of the antibodies on lymphocyte activity in lymphocyte effectorcells. IL-2 secretion was measured in the presence or absence of ananti-PD-L1 human monoclonal antibody (FIG. 10 ). The functional activityof the antibodies was assessed in an allogeneic mixed lymphocytereaction (MLR) consisting of purified CD4+ T lymphocytes and allogeneicdendritic cells. The antibodies used were the disclosed G12 antibody ascompared to prior disclosed antibodies 10A5 and 12A4(Bristol-Myers/Medarex) that were obtained via in-house production fromprior-disclosed antibody sequences (U.S. Patent Application 2009/0055944the disclosure of which is incorporated by reference herein). To preparethe dendritic cells, monocytes, purified using a discontinuous Percollgradient, were cultured with GM-CSF (1,000 U/ml) plus IL-4 (500 U/ml)for seven days. The CD4+ cells were prepared by negative selection usingbiotinylated antibodies reactive with CD8, CD16, CD19 and CD20. Removalof the reactive cells was achieved using biotin binding magnetic beads.The antibodies were added at the indicated concentrations to wellscontaining 10⁵ CD4+ cells labeled with carboxyfluorecein (CFSE) and 10⁴dendritic cells. After five days of culture, supernatants were harvestedfor cytokine determination.

Example 13

This example provides a mixed lymphocyte reaction (MLR) was employed todemonstrate the effect of blocking the PD-L1/PD-1 pathway by theanti-PD-L1 antibodies on lymphocyte effector cells. T cell activationwas measured in the presence or absence of the anti-PD-L1 humanmonoclonal antibody (FIG. 12 ). The functional activity of theantibodies was assessed in an allogeneic mixed lymphocyte reaction (MLR)consisting of purified CD4+ T lymphocytes and allogeneic dendriticcells. The antibodies used were the disclosed H6B1L, RSA1, RA3, RC5,SH1E2, SH1E4, SH1B11, and SH1C8 as compared to prior disclosedantibodies 10A5 (Bristol-Myers-Squibb/Medarex) and YW243.55S70(Roche/Genentech) that were obtained via in-house production fromprior-disclosed antibody sequences (U.S. Patent Application 2009/0055944and U.S. Patent Application US 2010/0203056; the disclosure of which areincorporated by reference herein). To prepare the dendritic cells,monocytes, purified using a discontinuous Percoll gradient, werecultured with GM-CSF (1,000 U/ml) plus IL-4 (500 U/ml) for seven days.The CD4+ cells were prepared by negative selection using biotinylatedantibodies reactive with CD8, CD16, CD19 and CD20. Removal of thereactive cells was achieved using biotin binding magnetic beads. Theantibodies were added at the indicated concentrations to wellscontaining 10⁵ CD4+ cells labeled with carboxyfluorecein (CFSE) and 10⁴dendritic cells. After five days of culture, the cells were collectedand stained for CD25 expression as a measure of cell activation. Cellactivation was measured by flow cytometry.

The results for cell activation are shown in FIG. 13 . With allanti-PD-L1 antibodies there was an increase in cell activation. In FIG.13 , the data are expressed as a percentage of test value with of therespect to that obtained in the absence of any added antibody. In thisway, the percent increase in cell activation was realized.

Example 14

The ability of anti-PD-L1 antibodies to modulate immune responsivenesswas assessed using a mixed lymphocyte reaction (MLR). With this assay,the effects anti-PD-L1 antibodies on cell activation and the productionof IL-2 were measured. The MLR was performed by culturing 10⁵ purifiedhuman CD4+ cells from one donor with 10⁴ monocyte derived dendriticcells prepared from another donor. To prepare the dendritic cells,purified monocytes were cultured with GM-CSF (1,000 U/ml) and IL-4 (500U/ml) for seven days. Anti-PD-L1 or control antibodies were added to theallogeneic MLR cultures at 10 μg/ml unless stated otherwise. Parallelplates were set up to allow collection of supernatants at day 3 and atday 5 to measure IL-2 using a commercial ELISA kit (Biolegend). Theantibodies used were the disclosed H6B1L, RSA1, RA3, RC5, SH1E2, SH1E4,SH1B11, and SH1C8 as compared to prior disclosed antibodies 10A5(Bristol-Myers-Squibb/Medarex) and YW243.55S70 (Roche/Genentech) thatwere obtained via in-house production from prior-disclosed antibodysequences (U.S. Patent Application 2009/0055944 and U.S. PatentApplication US 2010/0203056; the disclosure of which are incorporated byreference herein).

Production of IL-2 was enhanced by the addition of the anti-PD-L1antibodies.

Example 15

This example provides a mixed lymphocyte reaction (MLR) was employed todemonstrate the effect of blocking the PD-L1/PD-1 pathway by theanti-PD-L1 antibodies on lymphocyte effector cells. IFN-γ secretion wasmeasured in the presence or absence of the anti-PD-L1 human monoclonalantibody (FIG. 11 ). The functional activity of the antibodies wasassessed in an allogeneic mixed lymphocyte reaction (MLR) consisting ofpurified CD4+ T lymphocytes and allogeneic dendritic cells. Theantibodies used were the disclosed H6B1L, RSA1, RA3, RC5, SH1E2, SH1E4,SH1B11, and SH1C8 as compared to prior disclosed antibodies 10A5(Bristol-Myers-Squibb/Medarex) and YW243.55S70 (Roche/Genentech) thatwere obtained via in-house production from prior-disclosed antibodysequences (U.S. Patent Application 2009/0055944 and U.S. PatentApplication US 2010/0203056; the disclosure of which are incorporated byreference herein).

To prepare the dendritic cells, monocytes, purified using adiscontinuous Percoll gradient, were cultured with GM-CSF (1,000 U/ml)plus IL-4 (500 U/ml) for seven days. The CD4+ cells were prepared bynegative selection using biotinylated antibodies reactive with CD8,CD16, CD19 and CD20. Removal of the reactive cells was achieved usingbiotin binding magnetic beads. The antibodies were added at theindicated concentrations to wells containing 10⁵ CD4+ cells labeled withcarboxyfluorecein (CFSE) and 10⁴ dendritic cells. After five days ofculture, supernatants were harvested for cytokine determination.

Production of IFN-γ was enhanced by the addition of the anti-PD-L1antibodies.

Sequence Listing Heavy chain variable domain regionLight chain variable domain region E6QMQLVQSGAEVKKPGSSVKVSCKASGGTFNTYAISW DIVMTQTPYSVSASVGDRVTITCRASQEVSRWVRQAPGQGLEWMGGIIPLFGKADYAQKFQDRVTITA VAWYQQKPGQAPKSLIYASSRLQSGVPSRFTADESTSTAYMELSSLRSEDTAVYYCARDKGREELGGN SGSGTDFTLVISSLQPEDFATYYCQQYSRFPLYYYAVDVWGPGTTVTVSS SEQ ID NO. 1 TFGGGTKVEIK SEQ ID NO. 2 E7QVQLQQLGPGLVKPSQTLSLTCAISGDSVSSNSAAW QPVLTQPASVSGSPGQSITISCTGTSSDVGGYNWIRQSPSRGLEWLGRTYYRSKWYTNYAVSMRSRIT NYVSWYQQHPGKAPKLMVYDVSKRPSGVSNRFINPDTSKNQFSLQLNSVTPEDTAVYFCAGGNSSSHD SGSKSGNTASLTISGLQTEDEADYYCSSYTSSDYWGQGTLVTVSS SEQ ID NO. 3 NTRVFGTGTKLTVL SEQ ID NO. 4 E9EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISW DIVMTQSPSTLSASVGDRVTITCRASQSFTTYVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTT LAWYQQKPGKAPKLLIYQTSNLESGVPSRFSGDTSTSTAYMELRSLRSDDTAVYYCARDLFPTIFWEG SGSGTEFTLTISSLQPDDFATYYCQQYSRYWWGAFDIWGQGTMVTVSS SEQ ID NO. 5 SFGQGTRLEIK SEQ ID NO. 6 E11EVQLVQSGAEVKKPGASLKVSCKASGYTFNSYDINW AIQMTQSPSSLSASVGDRVTITCRASQSISSYVRQAPGQGLEWMGWINPNSGGTNYAQKFQGRVTMTR LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGDTSTSTVYMELSSLTSEDTAVYYCARDLFPHIYGNY SGSGTDFTLTISSLQPEDFATYYCQQSSSTPLYGMDIWGQGTTVTVSS SEQ ID NO. 7 TFGQGTKVEIK SEQ ID NO. 8 F1QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW QAVLTQPRSVSGSPGQSVTISCTGTSSDVGGYVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR NYVSWYQQHPGKAPKLMIYDVRTRPSGVSDRFDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW SGSKSGNTASLSISGLQAEDEADYYCSSHSSSGQGTLVTVSS SEQ ID NO. 9 TTVIFGGGTKLTVL SEQ ID NO. 10 F4EVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHW DIVMTQSPSSLSASVGDRVTITCRASQSISSYVRQAPGQGLEWMGWINPNSDNTGSAQKFQGRVFMTK LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGTTSLNTAYMELSGLRSEDTAIYYCARERSSGYFDFW SGSGTDFTLTISSLQPEDFATYYCQQSYSTPIGQGTLVTVSS SEQ ID NO. 11 TFGQGTRLEIK SEQ ID NO. 12 F7EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYWMSW QAVLTQPPSVSAAPGQRVTISCSGSNSNIADTVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISR YVSWYQQLPGTAPRLLIYDNDQRPSGIPDRFSDNAKNSLYLQMNSLRAEDTAVYYCAREGEHDAFDIW GSKSGTSATLGITGLQTGDEADYYCGTWDSSLGQGTMVTVSS SEQ ID NO. 13 SGVFGTGTKVTVL SEQ ID NO. 14 F8QVQLVQSGGGVVQPGRSPRLSCAASGFTFNTYGMHW QSVLTQPASVSGSPGQSVTISCTGTSSDVGGFVRQAPGKGLEWVAVISDGGNNKKYADSVKGRFTISR NSVSWYQQHPGKAPKLMIYDVSKRPSEISDRFDNAKNSLYLQMNSLRAEDTALYYCAKDIGESYYYYM SGSKSGNTASLTISGLQPEDEADYYCSSYTSSDVWGKGTTVTVSS SEQ ID NO. 15 STLVFGGGTKLTVL SEQ ID NO. 16 F11QVQLQQSGPGLVKPSQSLSLTCAISGDSLSSNSAAW SYVLTQPPSVSVSPGQTASISCSGYKLENKYVNWIRQSPSGGLEWLGRTYYRSKWYNEYVESLKSRIT SWYQQRAGQSPVLVIYQDNKRPSGIPERFSGSINSDISRNQFSLHLNSVTPEDTAVYYCASGTGARGM NSGNTASLTITGLQPEDEADYYCSAWDSSLRADVWGQGTTVTVSS SEQ ID NO. 17 WVFGGGTQLTVL SEQ ID NO. 18 G4QVQLQQSGPGLVKPSETLSLTCAISGDSVSENSAAW QPVLTQPPSVSVSPGQTASITCSGDELGNKYVNWIRQSPSGGLEWLGRTYYRSKWYNEYVESLKSRIT YWYQQKPGRSPVLVIYQDSKRPSGFPARFSGAINSDISRNQFSLHLNSVTPEDTAVYYCASGTGARGM NSGNTATLTISGTQAMDEADYFCQAWDSSTAWDVWGQGTTVTVSS SEQ ID NO. 19 VFGGGTKLTVL SEQ ID NO. 20 G9EVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHW DIVMTQSPSSLSASVGDRVTITCRASQSISSYVRQAPGQGLEWMGWINPNSDNTGSAQKFQGRVFMTK LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGTTSLNTAYMELSGLRSEDTAIYYCARERSSGYFDFW SGSGTDFTLTISSLQPEDFATYYCQQSYSTPIGQGTLVTVSS SEQ ID NO. 21 TFGQGTRLEIK SEQ ID NO. 22 G11QVQLVQSGAEVKKPGSSVKVSCKASGGTFSRYGVHW LPVLTQPASVSGSPGQSVTISCTGTSSDVGGHVRQAPGQGLEWMGRLIPIVSMTNYAQKFQDRVSITT NYVSWYQQHPGKAPKLMIYEVNKRPSGVPDRFDKSTGTAYMELRSLTSEDTALYYCASVGQQLPWVFF SGSKSDYTASLTISGLQPDDEADYFCSSYTATAWGQGTLVTVSS SEQ ID NO. 23 TTGVVFGTGTKVTVL SEQ ID NO. 24 G12EVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHW DIVMTQSPSSLSASVGDRVTITCRASQSISSYVRQAPGQGLEWMGWINPNSDNTGSAQKFQGRVFMTK LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGTTSLNTAYMELSGLRSEDTAIYYCARERSSGYFDFW SGSGTDFTLTISSLQPEDFATYYCQQSYSTPIGQGTLVTVSS SEQ ID NO. 25 TFGQGTRLEIK SEQ ID NO. 26 H1QVQLVQSGAEVKKPGASVKVSCKTSGNTFTNYYMHW DIVMTQSPPSLSASVGDRVTITCRASQSISSYVRQAPGQGLEWMGIMNPSGGSTSYAQKFQGRVTMTR LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGDKSTSTVYMELSSLTSEDTAVYYCARDLFPHIYGNY SGSGTDFTLTISSLQPEDFATYYCQQSYSTPYYGMDIWGQGTTVTVSS SEQ ID NO. 27 TFGQGTKVEIK SEQ ID NO. 28 H3QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW QSVVTQPPSVSAAPGQKVTISCSGSTSNIENYVRQAPGQGLEWMGGIIPIFGTASYAQKFQGRVTITA SVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSDESTTTAYMELSSLRSEDTAVYYCAREGPEYCSGGT GSKSGTSATLGITGLQTGDEADYYCGTWDNRLCYSADAFDIWGQGTMVTVSS SEQ ID NO. 29 SSVVFGGGTKVTVL SEQ ID NO. 30 H4QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW QPVLTQPPSVSAAPGQKVTISCSGSSSNIGNSVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITA HVSWFQQLPGTAPKLVIYDNDKRPSGIADRFSDKSTSTAYMELSSLRSEDTAVYYCARSESGSYSHDY GSKSGTSATLGITGLQTGDEADYYCGTWDSSLWGQGTTVTVSS SEQ ID NO. 31 SAGVFGGGTKLTVL SEQ ID NO. 32 H5QVQLVESGAEVKKPGASVKVSCKASGYTFTSYYIHW QAVVTQPPSASGTPGQRVTISCSGSSSNVGVNVRQAPGQGLEWMGilNPSGGSTTYAQKFQGRVSMTR HVFWYQHLPGMAPKLLIHRTNQWPSGVPDRFSDTSTRTVYMELSGLISDDTAIYYCARDDDFYSGYPG GSKSGTSATLGITGLQTGDEADYYCGTWDSSLDYWGQGTLVTVSS SEQ ID NO. 33 SAVFGGGTKLTVL SEQ ID NO. 34  H6QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW SYELMQPPSVSVAPGKTATIACGGENIGRKTVVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITA HWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSDESTSTAYMELSSLRSEDTAVYYCARGNIVATITPL NSGNTATLTISRVEAGDEADYYCQVWDSSSDHDYWGQGTLVTVSS SEQ ID NO. 35 RIFGGGTKLTVL SEQ ID NO. 36 H10EVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYSMNW EIVLTQSPSSLSASIGDRVTLTCRASQSIRRFVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTISR LNWYQQKPGKAPELLIYTASSLQSGVPSRFSGDNAKNSLYLQMNSLRDEDTAVYYCARGDYYYGMVWG DSGSGTDFTLTINSLQPEDFATYYCQQSYAVSQGTTVTVSS SEQ ID NO. 37 PYTFGQGTKVEIR SEQ ID NO. 38 H12QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW QSVVTQPPSVSAAPGQKVTISCSGSSSNIGNNVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITA YVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSDESTSTAYMELSSLRSEDTAVYYCARGDFWSGYRTY GSKSGTSATLGITGLQTGDEADYYCGTWDSSLYYYYGMDVWGQGTMVTVSS SEQ ID NO. 39 SAVVFGGGTKLTVL SEQ ID NO. 40 PDL-D2QVQLVQSGAEVKKPGASVKVSCKTSGYTFTSNAIGW ALTQPASVSGSLGQSITISCTGSSSDVGGYKYVRQAPGQGLEWMGWISAYNGNTNYAQNLQGRVTMTT VSWYQQHPGKAPKLMIYDVINRPSGVSSRFSGDTSTSTAYMELRSLRSDDTAVFYCARKGTGLHFDYW SKSANTASLTISGLQAEDEADYYCFSYSSRSTGQGTLVTVSS SEQ ID NO. 41 RIFGSGTKVTVL SEQ ID NO. 42 PDL-D11QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAW QTVVTQPPSVSKDLGQTATLTCTGNNNNVGNHNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRIT GAAWLQQHQGHPPKLLSYRNNNRPSGISERLSINPDTSKNQFSLQLNSVTPEDTAVYYCARGAAGRAF ASRSGNTASLTITGLQPEDEADYYCSAWDRSLDIWGQGTMVTVSS SEQ ID NO. 43 SAWVFGGGTKLTVL SEQ ID NO. 44 PDL-H1EVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYSMNW EIVLTQSPSSLSASIGDRVTLTCRASQSIRRFVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTISR LNWYQQKPGKAPELLIYTASSLQSGVPSRFSGDNAKNSLYLQMNSLRDEDTAVYYCARGDYYYGMVWG DSGSGTDFTLTINSLQPEDFATYYCQQSYAVSQGTTVTVSS SEQ ID NO. 45 PYTFGQGTKVEIK SEQ ID NO. 46 RB4EVQLVESGGGLVQPGGSLRLSCAASGFYLGSYWMAW QSVLTQPASVSGSPGQSISVSCTGTSSDVGRYVRQAPGKGLEWVAAIRQDGSETIYVDSVKGRFIISR NFVSWYQQHPGKAPKLMVFDVSNRPSGISNRFDNGGNSVTLQMTTLRAGDTAVYYCARAHYFGFDNWG SGSKSGNTASLTISGLQAEDEADYYCSSYTTNQGTLVTVSS SEQ ID NO. 47 STYVFGSGTKVTVL SEQ ID NO. 48 RB11QMQLVQSGAEVKKPGASVKISCKASGYPFRNYYIHW QPVLTQPPSVSAAPGQKVTISCSGSSSNIANNVRQAPGQGLEWVGIINPDGGTITYAGKFQGRVSMTR YVSWYQQLPGTAPKLLIFANNKRPSGIPDRFSDTSTSTVYMELSSLTSEDTAVYYCARDLFPHIYGNY GSKSGTSAALDITGLQTGDEADYYCGTWDSDLYGMDIWGQGTTVTVSS SEQ ID NO. 49 RAGVFGGGTKLTVL  SEQ ID NO. 50 RC5EVQLLESGGGVVQPGGSLRLSCAASGFTFSSYWMSW AIRMTQSPSSLSASVGDRVTITCRASQSISSYVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISR LNWYQQKPGKAPKLLIYTTSSLKSGVPSRFSGDNSKNTVSLQMNSLRAEDTAVYYCAKDRYYNFPLGM SGSGTDFTLTISRLQPEDFATYYCQQSYSSTWDVWGQGTTVTVSS SEQ ID NO. 51 TFGRGTKVEIK SEQ ID NO. 52 RF5EVQLLESGAEVKKPGSSVKVSCKSSGDTFTNFAINW QSVLTQPASVSGSPGQSITISCTGTSSDVGSYIRQAPGQGLEWMGRIIPLFGTTNYAQKFQGRVTITA NLVSWYQQYPGKAPKLMIYEVSERPSGVPDRFDESTSTAFMDLNSLTSEDTAVYYCARTLGGDYYDSR SGSKSGNTASLTVSGLQAEDEADYYCSSYTDSGYYNWGQGTLVTVSS SEQ ID NO. 53 NNFRVFGGGTKLTVL SEQ ID NO. 54 RG9QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSVVW EIVMTQSPSSLYASVGDRVTITCRASQSISSYNWFRQSPSRGLEWLGRAYYRSKWYNDYAVSVKSRIT LNWYQQKPGKVPKLLIYAASSLQSGVPSRFSGINPDTSKNQLSLQLNSVTPEDTAVYYCAKGLDVWGQ SGSGTDFTLTISGLQPEDFATYYCQQSYTPAWGTTVTVSS SEQ ID NO. 55 TFGQGTKLEIK SEQ ID NO. 56 RD1QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW QSVVTQPPSVSAAPGQKVTISCSGSSSNIGNNVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITA YVSWYQQVPGTAPKLLIYDNDKRPSGIPDRFSDESTSTAYMELSSLRSEDTAVYYCARDGIVADFQHW GSKSGTSATLAITGLQTGDEADYYCGTWDSSLGQGTLVTVSS SEQ ID NO. 57 NAWVFGGGTKLTVL SEQ ID NO. 58 RF11QVQLVQSGAEVKKPGASVRVSCKASGGTFSSYAISW QSVLTQPPSVSAAPGQKVTISCSGSSSNIENNVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITA YVSWYQHLPGTAPKLLIYDDFKRPSGIPDRFSDESTSTAYMELSSLRSEDTAVYYCARDGIVADFQHW GSKSGTSATLGITGLQTGDEADYYCGTWDSSLGQGTLVTVSS SEQ ID NO. 59 SAVVFGGGTKLTVL SEQ ID NO. 60 RH11QMQLVQSGAEVKKPGSSVKVSCKASGGTFNSYPISW QSVLTQPPSASGSPGQSVTISCTGTSSDVGGYVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITA NYVSWYQQHPGKAPKLMIYEVSKRPSGVPDRFDESTSTAYMELSSLRSEDTAMYYCAKNHPTATLDYW SGSKSGNTASLTVSGLQAEDEADYYCSSYAGSGQGTLVTVSS SEQ ID NO. 61 NNLGVFGGGTKLTVL SEQ ID NO. 62 RD9QVQLVQSGGNLVKPGGSLRLSCAASGFSFSSYDMNW DIQLTQSPSSLSASVGDRVTITCRASQGISSWVRQAPGRGLEWVSSISGTGRYEYYSPSVKGRFTISR LAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGDNANTSLYLQMNSLTADDTAVYFCTRGDILTGASAM SGSGTDFTLTISSLQPEDFATYYCQQANSFPLDVWGQGTTVTVSS SEQ ID NO. 63 TFGGGTKVEIK SEQ ID NO. 64 RE10EVQLLESGGNLVKPGGSLRLSCAASGFSFSSYDMNW DVVMTQSPSTLSASVGDRVTITCRASQSIGTWVRQAPGRGLEWVSSISGTGRYEYYSPSVKGRFTISR LAWYQQKPGKAPNLLIYKASSLESGVPSRFSGDNANTSLYLQMNSLTADDTAVYFCTRGDILTGASAM SGSGTEFTLTISSLQPDDFATYYCQQANSFPLDVWGQGTTVTVSS SEQ ID NO. 65 TFGGGTKVEIK SEQ ID NO. 66 RA3QMQLVQSGAEVKKPGSSVKVSCKASGGTFSRYGVHW DIQMTQSPSSLSASVGDRVTITCQASQDISNYVRQAPGQGLEWMGRLIPIVSMTNYAQKFQDRVSITT LNWYQQKPGKAPKLLIYDASTLQSGVPSRFSGDKSTGTAYMELRSLTSEDTALYYCASVGQQLPWVFF SGSGTDFTLTISSLQPEDFATYYCQQSYSSHWAWGQGTLVTVSS SEQ ID NO. 67 TFGQGTKVEIK SEQ ID NO. 68 RG1EVQLVQSGAEVKKPGSSVKVSCKASGGTFSRYGVHW QSVVTQPPSVSGAPGQRVTISCTGSSSNIGAGVRQAPGQGLEWMGRLIPIVSMTNYAQKFQDRVSITT YGVHWYQHLPGSAPKLLIYGNSNRPSGVTDRIDKSTGTAYMELRSLTSEDTALYYCASVGQQLPWVFF SGSKSGTSASLAITGLQAEDEAVYYCQSYDSSAWGQGTLVTVSS SEQ ID NO. 69 LSTSVVFGGGTKLTVL SEQ ID NO. 70 RB1QMQLVQSGGGLIQPGGSLRLSCAASGFTFSSYAMHW QAGLTQPASVSGSPGQSITISCTGTSSDVGGYVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR NYVSWYQQHPGKAPKLMIYDVTKRPSGVSNRFDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW SGSKSGNTASLTISGLQAEDEANYYCSSYTSRGQGTLVTVSS SEQ ID NO. 71 STSVLFGGGTKLTVL SEQ ID NO. 72 RG7EVQLVESGGGVVLPGRSLRLSCAASGFTFSSYAMHW QPVLTQPPSVSEAPRQRVTISCSGSSSNIGHNVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR AVTWYQQVPGKAPKLLIYYDDLLPSGVSDRFSDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW GSKSGTSASLAISGLQSEDEADYYCAAWDDSLGQGTLVTVSS SEQ ID NO. 73 NGWVFGGGTKLTVL SEQ ID NO. 74 RA6QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW QAGLTQPASVSGSPGQSITISCTGTSSDVGGYVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR NYVSWYQQHPGKAPKLMIYDVSNRPSGVPDRFDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW SGSKSGNTASLTISGLQAEDDADYYCASYTSTGQGTLVTVSS SEQ ID NO. 75 STLGVVFGGGTKLTVL SEQ ID NO. 76 RA8QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW QPVLTQPASVSGSPGQSITISCTGTSSDVGGYVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR NYVSWYQHHPGKAPKLMIFDVNKRPSGVSNRFDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW SGSKSGNTASLTISGLQAEDEADYYCNSYTTSGQGTLVTVSS SEQ ID NO. 77 STYVVFGGGTKLTVL SEQ ID NO. 78 RA9QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR TVHWYQQLPGTAPKVLIYTNNQRPSGVPDRFSDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW GSKSGTSASLAISGLQSEDEADYYCAAWDGRLGQGTLVTVSS SEQ ID NO. 79 QGWVFGGGTKLTVL  SEQ ID NO. 80 RB5QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW QSVVTQPPSVSAAPGQKVTISCSGSNSNIANNVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR YVSWYQQLPGTAPKLLIYDSNKRPSGIPDRFSDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW GSKSGTSATLGITGLQTGDEADYYCGSWDSSLGQGTLVTVSS SEQ ID NO. 81 SVWMFGGGTKLTVL SEQ ID NO. 82 RB8QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW LPVLTQPRSVSGSPGQSVTISCTGTSSDVGGYVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR NYVSWYQQHPGKAPKLMIYDVTKRPSGVPDRFDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW SGSKSGNTASLTISGLQAEDEADYYCSSYTGSGQGTLVTVSS SEQ ID NO. 83 STLGPVFGGGTKLTVL SEQ ID NO. 84 RC8EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW QSVLTQPPSVSAAPGQKVTISCSGNSSNIGNNVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR YVSWYQQLPGTAPKLLIYDNDKRPSGIPDRFSDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW GSKSGTSASLAISELRFEDEADYYCAAWDDTLGQGTLVTVSS SEQ ID NO. 85 SGHVFGPGTKLTVL SEQ ID NO. 86 RC10EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW SYELMQPPSVSVPPGETARITCGGNNIGNKNVVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR HWYQQKPGQAPVLVVREDSARPAGIPERFSGSDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW NSGNSATLTISRVEAGDEADYYCQVWDNTSDHGQGTLVTVSS SEQ ID NO. 87 VVFGGGTKLTVL SEQ ID NO. 88 RD2QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW SYELMQPPSVSEVPGQRVTISCSGSSSNIGNNVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR AVNWFQQLPGKAPKLLVYYDDWVPSGISGRFSDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW ASKSGTSASLAISGLQSGDEGDYYCAVWDDRLGQGTLVTVSS SEQ ID NO. 89 SGVVFGGGTKLTVL SEQ ID NO. 90 RE8QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW QSVVTQPPSVSAAPGQKVTISCSGSSSNIGNNVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR YVSWYQQLPGTAPTLLIYDSNKRPSVIPDRFSDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW GSKSGTSATLGITGLQTGDEADYYCGTWDDSLGQGTLVTVSS SEQ ID NO. 91 NGWVFGGGTKLTVL SEQ ID NO. 92 RE9EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW QSALTQPASVSGSPGQSITISCTGTSSDVGGYVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR NYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW SGSKSGNTASLTISGLQAEDEADYYCSSYRSSGQGTMVTVSS SEQ ID NO. 93 TLGPVFGGGTKLTVL SEQ ID NO. 94 RG12QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW QAGLTQPPSASGSPGQSVTISCTGTSSDVGGYVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR NYVSWYQQHPGKAPKLMIYDVSNRPSGVPDRFDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW SGSKSGNTASLTISGLQAEDEADYYCSSYTSSGQGTLVTVSS SEQ ID NO. 95 STLVVFGGGTKLTVL SEQ ID NO. 96 RSA1EVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYSMNW NIQMTQSPSSVSASVGDRVTITCRASQDISRWVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTISR LAWYQQKPGKAPKLLIYAASSLQSGVPSRDFSDNAKNSLYLQMNSLRDEDTAVYYCARGDYYYGMVWG GSGSGTDFALTISSLQPEDFATYYCQQADSFFQGTTVTVSS SEQ ID NO. 97 SITFGQGTRLEIK SEQ ID NO. 98 R2A7QVQLVQSGSEVKKPGASVKVSCRASGYLFTNYGISW AIQLTQSPATLSLSPGERATLSCRASQSVGVYVRQAPGQGLEWMGWVSAHGEFTKYAPSLQDRVTMTS LAWYQQKPGQSPRLLIYDTSKRATGIPDRFSADISTTTAYMELRSLRSDDAGVYYCARDRGADHFDTW SGSGTDFTLTISRLEPEDFAVYYCHQRHSWPTGQGTLVTVSS SEQ ID NO. 99 TFGQGTRLEIK SEQ ID NO. 100 R2B12EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHW NIQMTQSPSSLSASVGDRVTITCRASQSISSYVRQAPGQGLEWMGMINPSSATTTYTQKFQGRVSMTR LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGDTSTSTVYMELSSLTSEDTAVYYCARDLFPHIYGNY SGSGTDFTLTISSLQPEDFATYYCQQSYSTLTYGMDIWGQGTTVTVSS SEQ ID NO. 101 FGGGTKVEIK SEQ ID NO. 102 R2C9EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSHVISW QSVLTQPASVSGSPGQSITISCTGTSSDVGDYVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITA NLVSWYQQHPGKAPKLIIYEVNKRPSGVSNRFDESTSTAYMELSSMRSEDTAVYYCATSGVVAATHFG  SGSKSGNTASLTISGLQAEDEADYYCSSYAGYYWGQGTLVTVSS SEQ ID NO. 103 NNLYVFGTGTKVTVL SEQ ID NO. 104 R2D5QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW QSALTQPPSASGSPGQSVTISCTGTSSDVGGYVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITA NYVSWYQQHPGKAPKLIIYDVNMRPSGVPDRFDESTSTAYMELSSLRSEDTAVYYCARGASGSYFITT SGSKSGNTASLTISGLQAEDEADYYCSSYAGLYVDYWGQGTLVTVSS SEQ ID NO. 105 YFPLFGGGTQLTVL SEQ ID NO. 106 R2D7EVQLVESGGGLVQPGGPLRLSCAASGFTLSSYWMSW DIVMTQSPSSLSASVGDRVTITCRASQSISSYVRQAPGKGLEWVANIKYDGSETYYADSVKGRFTISR LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGDNAKNSLYLQMNRLRLEDTAVYYCAREVSSAATSPL SGSGTDFTLTISSLQPEDFATYYCQQSHSSRYDRWGRGTLVTVSS SEQ ID NO. 107 TFGQGTKLEIK SEQ ID NO. 108 R2F4EVQLVQSGAEVKKPGSSVKVSCKASGGTFSRYGVHW QSVVTQPPSVSGAPGQRVTISCTGSSSNIGAGVRQAPGQGLEWMGRLIPIVSMTNYAQKFQDRVSITT YGVHWYQHLPGSAPKLLIYGNSNRPSGVTDRIDKSTGTAYMELRSLTSEDTALYYCASVGQQLPWVFF SGSKSGTSASLAITGLQAEDEAVYYCQSYDSSAWGQGTLVTVSS SEQ ID NO. 109 LSTSVVFGGGTKLTVL SEQ ID NO. 110 R2A10EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYAMHW QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR TVHWYQQLPGTAPKVLIYTNNQRPSGVPDRFSDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW GSKSGTSASLAISGLQSEDEADYYCAAWDGRLGQGTLVTVSS SEQ ID NO. 111 QGWVFGGGTQLTVL SEQ ID NO. 112 R2E2EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW QAGLTQPPSASGTPGQRVTISCFGSSSDIGSNVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR TVNWYQQVSGRAPKLLLYTNGQRPSGVPDRFSDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW GSKSGSSASLAISGLQSEDEADYYCASWDDSLGQGTLVTVSS SEQ ID NO. 113 KGYVFGTGTKVTVL SEQ ID NO. 114 R3B8EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW QSVLTQPPSVSAAPGQKVTISCSGSSSNIGNSVRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITA YVSWYQHLPGTAPKLLIYDNNKRPSGIPDRFSDKSTSTAYMELSSLRSEDTAVYYCARVGGGAQTPFD GSKSATSATLGITGLQTADEADYYCGTWDSSLYWGQGTLVTVSS SEQ ID NO. 115 GVVFGGGTKLTVL SEQ ID NO. 116 R3C3QVQLVQSGSEVKRPGASVRVSCKASGYIFSQYTIHW QSALTQPASVSGSPGQSITISCTGTSSDVGGYVRQAPGERLEWLGWINAVTGNTKYAQKFQGRVTITM NYVSWYQQHPGKAPKLMIYNVSKRPSGVSNRFDSSASTAFMEMSSLRSEDAGVYFCARDMVPFGGEIK SGSKSGNTASLTISGLQAEDEADYYCSSYTSSYGFDFWGQGTMITVSS SEQ ID NO. 117 STFVFGTGTKVTVL SEQ ID NO. 118 R3E9QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHW SYELMQPPSVSVAPGETARITCGGNNIGSKSVVRQAPGKGLEWVALISYDGSNKYYADSMKGRFTISR HWYQQKPGQAPILVIYYDSGRPSGIPERFSGSDNSKNTLFLQMNSLRAEDTAVYYCAKTLMPASIMGY NSGNTATLTISRAEAGDEADYYCHVWDSYTDHFTHWGQGTLVTVSS SEQ ID NO. 119 VVFGGGTKLTVL SEQ ID NO. 120 R3E10QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHW QPVLTQPPSLSVAPGKTASIACGGNNIGSKRVVRQAPGQGLEWMGIINPSDGSTSYAQKFQGRVTMTR HWYQQKPGQAPVLVIYYESDRPSGIPERFSGTDTSTSTVYMELSSLRSEDTAVYYCARGYYGSGIAMD ISQNTATLSISRVEAGDEADYYCQVWDRSSAHVWGQGTTVTVSS SEQ ID NO. 121 VVFGGGTKVTVL SEQ ID NO. 122 R3F7QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW AIQMTQSPSSLSASVGDRVTITCRASQSISTYVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITA LNWYQQKPGKAPKLLIYAASSLQNGVPSRFSGDESTSTAYMELSSLRPEDTAVYYCARDNGDLGFDYW SGSGTDFTLTISSLQPEDFATYYCQQSYSTPRGQGTLVTVSS SEQ ID NO. 123 TFGPGTKVDIK SEQ ID NO. 124 R3F10EVQLVESGGGLIQPGGSLRLSCAASGFTVSSNYMSW DIQMTQSPSSLSASVGDRVTITCQASQDISNYVRQAPGKGLEWVSVIYSGGTIYYADSVKGRFTISRD LNWYQQKPGKAPKLLIFAGSNLQSGVPSRFSGSSKNTLYLHMNSLRAEDTGVYYCAKGVGSWSIFDYW SGSGTDFTLTITSLQPEDFATYYCQQSYTTPTGQGTLVTVSS SEQ ID NO. 125 FGQGTKVEIK SEQ ID NO. 126 R4B10EVQLVESGAELKKPGSSMKVSCKASGGTFSSYAISW QSVVTQPASVSGSPGQSITISCTGTSSDVGSYVRQAPGQGLEYIGRIIPIFGVTYYAQKFQGRVTISA NLVSWYQQHPGKAPKLMIYEGSKRPSGVSTRFDKSTSTVYLDLRSLRSEDTAVYYCARDLGGGDGDWG SGSKSGNTASLTISGLQAEDESDYYCSSYTGSQGTLVTVSS SEQ ID NO. 127 AWVFGGGTKLTVL SEQ ID NO. 128 R4H1EVQLVQSGAEVKKPGSSVKVSCKASGYTFTGYYMHW QSVVTQPPSVSATPGQKVTISCSGSDSNIGNNVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVTITA YVSWFLQLPGTAPKLLIHNNDQRPSGVPDRFSDESTSTAYMELSSLRSEDTAVYFCVTSAWSDWGQGT GSKSGTSASLAITGLQAEDEADYYCQSFDDSLLVTVSS SEQ ID NO. 129 RGYLFGTGTKVTVL SEQ ID NO. 130 R4A11EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMSW QAVLTQPPSVSAAPGQKVTISCSGGSSNIANNVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISR YVSWYQHLPGTAPKLLIYDDNKRPSGIPDRFSDNSKNTLYLQMNSLGAEDTAVYYCAKGFYYPDHWGQ GSKSGTSATLGITGLQTGDGADYYCGTWDNSLGTLVTVSS SEQ ID NO. 131 NSDWVFGGGTKL SEQ ID NO. 132  R3D2EVQLVESGGGVVQPGGSLRLSCEVSGFIFSDYGMHW QSVLTQPPSVSVAPGKTARITCGGNNIGSKSVVRQAPGKGLEWVSSISSSSSYIYYADSVKGRFTISR HWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSDNAKNSLYLQMNSLRAEDTAMYYCARSWNYGRFFDY NSGNTATLTISRVEAGDEADYYCQVWDSSSDHWDQGTLVTVSS SEQ ID NO. 133 YVFGTGTKLTVL SEQ ID NO. 134 R5B8EVQLVESGGGLVQPGGSLRLSCAASGFTSSRNWMHW VIWMTQSPSSLSASVGDRVTITCRASQTISSYVRLAPGKGLVWVSLIAPDGSLTTYADSVKGRFTISR LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGDTAKNSVQLLLNSLRAEDTGLYFCAREAGVSGGLDV SGSGTDFTLTISSLQPEDFATYYCQQANSFPLWGQGTLVTVSS SEQ ID NO. 135 TFGGGTKVEIK SEQ ID NO. 136 SH1A1QEVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW QSVLTQPPSVSAAPGQKVTISCSGNNSNIANNVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITA YVSWYQQLPGTAPKLLIYDNNYRPSGIPDRFSDKSTSTAYMELSSLRSEDTAVYYCAREGTIYDSSGY GSKSGTSATLDITGLQTGDEADYYCGVWDGSLSFDYWGQGTLVTVSS SEQ ID NO. 137 TTGVFGGGTKLTVL SEQ ID NO. 138 SH1B7B(K)EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW AIQMTQSPSSLSASVGDRVTITCRASQGISNYVRQAPGQGLEWMGilNPSGGSTSYAQKFQGRVSMTR LAWYQQKPGKVPKLLIYAASTLESGVPSRFSGDTSTSTVYMELSSLTSEDTAVYYCARDLFPHIYGNY SGSGTDFTLTISSLQPEDLATYYCQQLHTFPLYGMDIWGQGTTVTVSS SEQ ID NO. 139 TFGGGTKVEIK SEQ ID NO. 140 SH1C1QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW QPVLTQPPSASGSPGQSVTISCTGTSSDVGAYVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITA NFVSWYRQHPGKAPKLMIYEVNKRPSGVPDRFDKSTSTAYMELSSLRSEDTAVYYCARLAVPGAFDIW SGSKSGNTASLTVSGLQAEDEADYYCSSYAGTGQGTMVTVSS SEQ ID NO. 141 NSLGIFGTGTKLTVL SEQ ID NO. 142 SH1C8EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW QSVVTQPPSVSAAPGQKVTISCSGSSSDIGNHVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISR YVSWYQQLPGTAPKLLIYDNNQRPSGIPDRFSDNSKNTLYLQMNSLRAEDTAVYYCARGQWLVTELDY GSKSGTSATLAITGLQTGDEADYYCGTWDNSLWGQGTLVTVSS SEQ ID NO. 143 SPHLLFGGGTKLTVL SEQ ID NO. 144 SH1E10EVQLVESGSEVEKPGSSVKVSCKASGGTFSDSGISW QSVLTQPPSVSAAPGQKVTISCSGSSSNMGNNVRQAPGQGLEWMGGIIPMFATPYYAQKFQDRVTITA YVSWYKQVPGTAPKLLIYENDKRPSGIPDRFSDESTSTVYMELSGLRSDDTAVFYCARDRGRGHLPWY GSKSGTSATLGITGLQTGDEADYYCGTWDNSLFDLWGRGTLVTVSS SEQ ID NO. 145 SGFVFASGTKVTVL SEQ ID NO. 146 SH1E2EVQLVESGAEVKKPGSSVKVSCKASGGTFSSYAISW QSALTQPASVSGSLGQSVTISCTGSSSDVGSYVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITA NLVSWYQQHPGKAPNLMIYDVSKRSGVSNRFSDESTSTAYMELSSLRSEDTAVYYCARAPYYYYYMDV GSKSGNTASLTISGLQAEDEADYYCSSYTGISWGQGTTVTVSS SEQ ID NO. 147 TVVFGGGTKLTVL SEQ ID NO. 148 SH1A9EVQLLESGAEVKKPGSSVKVSCKASGGTLSRYALSW QSVLTQPASVSGSPGQSITISCTGTSSDVGSYVRQAPGQGPEWVGAIIPIFGTPHYSKKFQDRVIITV NLVSWYQQHPGKAPKLMIYEVSKRPSGVSNRFDTSTNTAFMELSSLRFEDTALYFCARGHDEYDISGY SGSKSGNTASLTISGLQAEDEADYYCSSYGGFHRLDYWGQGTLVTVSS SEQ ID NO. 149 NNLLFGGGTKLTVL SEQ ID NO. 150 SH1B11QVQLVQSGSELKKPGSSVKVSCKASGYSFSGYYIHW DIVMTQSPSSLSASIGDRVTITCRASQRISAYVRQAPGQGLEWMGWIDPNSGVTNYVRRFQGRVTMTR VNWYQQKPGKAPKVLIYAASSLRSGVPSRFSGDTSLSTAYMELSGLTADDTAVYYCARDENLWQFGYL SGSGTDFTLTISSLQPEDFATYYCQQTYSSPWDYWGQGTLVTVSS SEQ ID NO. 151 TFGQGTKVEIK SEQ ID NO. 152 SH1E4QVQLVQSGAEVKKPGSSVKVSCKASGGTFSRYGVHW QSVLTQPPSASGSPGQSVTISCTGTSSDIGGYVRQAPGQGLEWMGRLIPIVSMTNYAQKFQDRVSITT DSVSWYQQHPGKAPKLMIYDVSKRPSGVSNRFDKSTGTAYMELRSLTSEDTALYYCASVGQQLPWVFF SGSKSGNTASLTISGLQAEDEADYYCSSYTSSAWGQGTLVTVSS SEQ ID NO. 153 SIFFYVFGTGTKVTVL SEQ ID NO. 154 SH1B3QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW LPVLTQPASVSGSPGQSITISCTGTTSDIGGYVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR DYVSWYQQHPGKAPKLMIYDVSKRPSGVSNRFDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW SGSKSGNTASLTISGLQAEDEADYYCSSYTSSGQGTLVTVSS SEQ ID NO. 155 STHVFGTGTKLTVL SEQ ID NO. 156 SH1D1EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW QSALTQPASVSGSPGQSITISCTGTSSDVGGYVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR NYVSWYQQHPGKAPKLMIYDVSNRPSGVSNRFDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW SGSKSGNTASLTISGLQAEDEADYYCSSYRSSGQGTLVTVSS SEQ ID NO. 157 TLGPVFGGGTKLTVL SEQ ID NO.158 SH1D2QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW QAGLTQPPSVSEAPRQRVTISCSGSSSNIGNNVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR AVNWYQQLPGKAPKLLIYYDDLLPSGVSDRFSDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW GSKSGTSASLAISGLQSEDEADYYCAAWDDSLGQGTLVTVSS SEQ ID NO. 159 NGYVFGTGTKLTVL SEQ ID NO. 160 SH1D12EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW QSALTQPRSVSGSPGQSVTISCTGTSSDVGGYVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR NYVSWYQQHPGKAPKLMIYDVSKRPSGVPDRFDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW SGSKSGNTASLTISGLQAEDEADYYCSSYTSSGQGTLVTVSS SEQ ID NO. 161 TTHVFGTGTKVTVL SEQ ID NO. 162 SH1E1EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW QSVVTQPPSVSAAPGQKVTISCSGSSSNIGNNVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR YVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW GSKSGTSATLGITGLQTGDEADYYCGTWDSSLGQGTLVTVSS SEQ ID NO. 163 SVWVFGGGTQLTVL SEQ ID NO. 164 SH1G9QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMHW QSVLTQPASVSGSPGQSITISCTGTSSDVGGYVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR NYVSWYQQHPGRAPRLMIYDVSNRPSGVSNRFDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW SGSKSGNTASLTISGLQAEDEGDYYCSSYTSGGQGTLVTVSS SEQ ID NO. 165 GTLGPVFGGGTKLTVL SEQ ID NO. 166 SH1A11EVQLVQSGGGLVQPGGSLRLSCAASGFTFSDYGMHW QAGLTQPPSASGTPGQRVTISCSGSSSNIGSNVRQPPGKGLEWLAVISYDGSYKIHADSVQGRFTISR TVNWYQQLPGTAPKLLIYSNNQRPSGVPDRFSDNAKNSVFLQMNSLKTEDTAVYYCTTDRKWLAWHGM GSKSGTSASLAISGLQSEDEADYYCAAWDDSLDVWGQGTTVTVSS SEQ ID NO. 167 NGWVFGGGTKLTVL SEQ ID NO. 168 SH1C2EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW AIRMTQSPSSLSASVGDRVTITCRASQSISNYVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITA LNWYQQRPGKAPNLLIYAASSLQSGVPSRFSGDESTSTAYMELSSLRSEDTAVYYCARDGIVADFQHW SGSGTDFTLTISSLQPEDFATYYCQQTYSTPYGQGTLVTVSS SEQ ID NO. 169 TFGQGTKLEIK SEQ ID NO. 170 SH1G8EVQLVESGAEVKKPGASVKVSCKASGDTFSRYGITW QSVLTQPASVSGSPGQSITISCTGTSSDVGGYVRQAPGRGLEWMGNIVPFFGATNYAQKFQGRLTITA NYVSWYRQHPGKAPKLMIYDVSYRPSGVSNRFDKSSYTSYMDLSSLRSDDTAVYYCARDHFYGSGGYF SGSKSGNTASLTISGLQAEDEADYYCSSYTDSDYWGQGTLVTVSS SEQ ID NO. 171 STRYVFGTGTKLTVL SEQ ID NO. 172 SH1H2EVQLLESGAEVKKPGASVKVSCKASGYTFNSYDINW QPVLTQPPSASGTPGQRVAISCSGSRSNIEINVRQAPGQGLEWMGGIIPVFGTANYAESFQGRVTMTA SVNWYQQLPGTAPKLLIYDNNKRPSGIPDRFSDHSTSTAYMELNNLRSEDTAVYYCARDRWHYESRPM GSKSGTSATLGITGLQTGDEADYYCGSWDSSLDVWGQGTTVTVSS SEQ ID NO. 173 SADVFGTGTKLTVL SEQ ID NO. 174 SH1B10EVQLVESGGGLVRPGGSLRLACAASGFSFSDYYMTW QSVLTQPPSVSAAPGKKVTISCSGSSSNIGNNIRQAPGRGLEWIAYISDSGQTVHYADSVKGRFTISR YVSWYQQLPGTAPKLLIYRNNQRPSGVPDRFSDNTKNSLFLQVNTLRAEDTAVYYCAREDLLGYYLQS GSKSGTSASLAISGLQSEDEADYYCATWDDSLWGQGTLVTVSS SEQ ID NO. 175 NGWVFGGGTKLTVL SEQ ID NO. 176 SH1B7A(L)QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAW QSVVTQPPSVSGAPGQRVTISCTGSSSNIGAGNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRIT YDVHWYQQLPGTAPKLLIYGNNNRHSGVPDRFINPDTSKNQFSLQLNSVTPEDTAVYYCARDEPRAVA SGSKSGTSASLAITGLQAEDEAEFFCGTWDSRGSQAYYYYGMDVWGQGTTVTVSS SEQ ID NO. LTTYVFGSGTKLTVL SEQ ID NO. 178 177SH1E6 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSRYGVHWQSVVTQPPSVSAAPGQKVTISCSGSSSNIGNN VRQAPGQGLEWMGRLIPIVSMTNYAQKFQDRVSITTYVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFS DKSTGTAYMELRSLTSEDTALYYCASVGQQLPWVFFGSKSGTSATLGITGLQTGDEADYYCGTWDSSL AWGQGTLVTVSS SEQ ID NO. 179SAVVFGGGTKLTVL SEQ ID NO. 180 SH1C11EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHW VIWMTQSPSSLSASVGDRVTITCRASQSISSYVRQAPGQGLEWMGIINPSDGSTSYAQKFQGRVTMTR LNWYQQKPGKAPKLLIYEASTLESGVPSRFSGDTSTSTVHMELSSLRSEDTAVYYCARDLFPHIYGNY SGSGTEFTLTISSLQPEDFATYYCQQSYSTPYYGMDIWGQGTTVTVSS SEQ ID NO. 181 TFGQGTKLEIK SEQ ID NO. 182 SH1A2QMQLVQSGGGVVQPGRSLRLSCAASGFTFSSYAMHW QSVVTQPPSVSAAPGQKVTISCSGSSSNIGNNVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR YVSWYQQVPGTAPKLLIYDNNKRPSGIPDRFSDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW GSNSDTSATLGITGLQTGDEADYYCGTWDSSLGQGTLVTVSS SEQ ID NO. 183 SAWVFGGGTKLTVL SEQ ID NO. 184 SH1B1QVQLVQSGGGVVQPGRSLRLSCAASGFTFSSYAMHW QSVVTQPPSVSAAPGQKVTISCSGSSSNIGNNVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTISR YVSWYQQLPGTAPKLLIYDNNKRPSGIPDRFSDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDIDYW GSKSGTSATLGITGLQTGDEADYYCGTWDSSLGQGTLVTVSS SEQ ID NO. 185 SAGSVVFGGGTKLTVL SEQ ID NO. 186 R6B2EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW QPVLTQPRSVSGSPGQSVTISCTGTSSDVGGYVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITA NFVSWYQQNPGKAPKLMIYDVSKRPSGVPDRFDESTSTAYMELSSLRSEDTAVYYCARDGIVADFQHW SGSKSGNTASLTVSGLRAEDEADYYCASYAGGGQGTLVTVSS SEQ ID NO. 187 RTFVFGGGTKVTVL SEQ ID NO. 188 R6B7QMQLVQSGAEVKKPGSSVKVSCKASGGTFNSYPISW QSVLTQSPSSFSASTGDRVTITCRASQGISSYVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITA LAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGDESTSTAYMELSSLRSEDTAMYYCAKNHPTATLDYW SGSGTDFTLTISCLQSEDFATYYCQQYYSYPLGQGTLVTVSS SEQ ID NO. 189 TFGGGTKVTVL SEQ ID NO. 190 R6B11QVQLVQSGGGVVQPGRSLRLSCAASGFPFRSYDMHW LPVLTQPASVSASAGQSIAISCTGISSDIGDYVRQAPGEGLEWVALISSDGSNKYYLDSVKGRETISR NSVSWYQRHPGKAPKLIIYDVSSRPSGVADRFDNSKNTLYLQMNSLRAEDTAVYYCAKDLLPYSSSWD SGSKSGSTASLSISGLQAEDEADYYCASYTASYYYYYGMDVWGQGTTVTVSS SEQ ID NO. 191 DNPVFGGGTKLTVL SEQ ID NO. 192 R6D1EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHW SYELMQPPSVSVAPGKTATIACGGENIGRKTVVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISA HWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSDTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMD NSGNTATLTISRVEAGDEADYYCQVWDSSSDHYWGQGTLVTVSS SEQ ID NO. 193 RIFGGGTKLTVL SEQ ID NO. 194 R6C8EVQLVESGGGLVKPGGSRKLSCAASGFTFSNYGMHW QSVLTQPPSVSAAPGQEVTISCSGSNSNIGNNVRQAPEKGLEWVAYISSGSSTIYYADTVKGRFTISR YVSWYQQLPGTAPKLLIYDNNERPSGIPDRFSDNAKNTLFLQMTSLRSEDTAMYYCARRGLLLDYWGQ GSKSGTSATLGITGLQTGDEADYYCGTWDSSLGTTLTVSS SEQ ID NO. 195 SAGVFGGGTKLTVL SEQ ID NO. 196 R9G8EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISW QSVLTQPPSVSAAPGQEVTISCSGSNSNIGNNVRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVTMTT YVSWYQQLPGTAPKLLIYDNNERPSGIPDRFSDTSTSTAYMELRSLRSDDTAVYYCARDLFPTIFWEG GSKSGTSATLGITGLQTGDEADYYCGTWDSSLGAFDIWGQGTMVTVSS SEQ ID NO. 197 SAGVFGGGTKLTVL SEQ ID NO. 198 R7D1QVQLVQSGSEVEKPGSSVKVSCKASGGTFSDSGISW QSVLTQPPSVSAAPGQEVTISCSGSNSNIGNNVRQAPGQGLEWMGGIIPMFATPYYAQKFQDRVTITA YVSWYQQLPGTAPKLLIYDNNERPSGIPDRFSDESTSTVYMELSGLRSDDTAVFYCARDRGRGHLPWY GSKSGTSATLGITGLQTGDEADYYCGTWDSSLFDLWGRGTLVTVSS SEQ ID NO. 199 SAGVFGGGTKLTVL SEQ ID NO. 200 R7D2QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW AIRMTQSPSSLSASVGDRVTITCRASQSISNYVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITA LNWYQQRPGKAPNLLIYAASSLQSGVPSRFSGDESTSTAYMELSSLRSEDTAVYYCARDGIVADFQHW SGSGTDFTLTISSLQPEDFATYYCQQTYSTPYGQGTLVTVSS SEQ ID NO. 201 TFGQGTKLEIK SEQ ID NO. 202 R7E7EVQLLESGAEVKKPGSSVKVSCKASGGTFSSYAISW QSVLTQPPSVSAAPGQEVTISCSGSNSNIGNNVRQAPGQGLEWMGRIIPILGIADYAQKFQGRVTITA YVSWYQQLPGTAPKLLIYDNNERPSGIPDRFSDKFTSTAYMELSSLRSEDTAVYYCATVEGWGAVTTF GSKSGTSATLGITGLQTGDEADYYCGTWDSSLDYWGQGTLVTVSS SEQ ID NO. 203 SAGVFGGGTKLTVL SEQ ID NO. 204 R7F2QVQLVQSGAEVKKPGSSVKVSCKASGGTLSSYAISW QSVLTQPPSVSGAPGQRVTISCTGSSSNIGAGVRQVPGHGLEWMGRIISMLGVSNYAQNFQGRVTITA YDVYWYQHLLGKAPKLLIYGNSNRPSGVSDRFDKSTSTAYMELRSLTSDDTAVYYCATVTIFDGDYYA SASKSGTSVSLAITGLQAEDEADYYCQSYDSSMDVWGQGTTVTVSS SEQ ID NO. 205 LSGYVFGTGTKLTVL SEQ ID NO. 206 R7F7EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSHVISW QPVLTQPASVSGSPGQSITISCTGTSSDVGSYVRQAPGQGLEWMGIILPSFGKTNYAQKFQGRVTMTG NLVSWYQQHPGKAPKLMIYEVSKRPSGVSNRFDTSTSTVYMELSSLTSEDTAVYYCVREFSGGYFDYW SGSKSGNTASLTISGLQAEDEADYYCNTYTSSGQGTLVTVSS SEQ ID NO. 207 GTYVIGTGTKVTVL SEQ ID NO. 208 R9H2QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYVIHW QPVLTQPASVSGSPGQSITISCTGTSSDIGRYVRQAPGQRLEWMGWIHAGNGHTKYAQNFQGRVTITR NYVSWYQQHPGKAPKVMIYDVSNRPSGVSNRFDTSATTAYVEVSSLGSEDTALYYCAREGSDIGLDLH SGSKSGNTASLTISGLQAEDEADYYCSSYTSSYWGQGTLVTVSS SEQ ID NO. 209 STWVFGGGTKLTVL SEQ ID NO. 210 R9H6EVQLVQSGGGVVQPGRSLRLSCEASGFTFRNFAMHW QSVVTQPPSVSAAPGQKVTISCSGSSSNIGNNVRQAPGKGLEWAAVISVDGSREHYADSVKGRFTISR YVSWYQQLPGTAPKILIYDNDKRPSGIPDRFSDNSQNTVYLQMNGLRPEDTAEYYCAREGEGSTWSSF GSKSGTSATLGITGLQTGDEADYYCGTWDRSLDYWGQGTLVTVSS SEQ ID NO. 211 SGYVFGTGTKVTVL SEQ ID NO. 212 H6B1LQMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAYSW SYELMQPPSVSVAPGKTATIACGGENIGRKTVVRQAPGQGLEWMGGIIPSFGTANYAQKFQGRVTITA HWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSDESTSTAYMELSSLRSEDTAVYYCARGPIVATITPL NSGNTATLTISRVEAGDEADYYCLVWDSSSDHDYWGQGTLVTVSS SEQ ID NO. 213 RIFGGGTKLTVL SEQ ID NO. 214 H6A1QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAYSW SYELMQPPSVSVAPGKTATIACGGENIGRKTVVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITA HWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSDESTSTAYMELSSLRSEDTAVYYCARGPIVATITPL NSGNTATLTISRVEAGDEADYYCQVWDSSSDHDYWGQGTLVTVSS SEQ ID NO. 215 RIFGGGTKLTVL SEQ ID NO. 216 H6B1QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAYSW SYELMQPPSVSVAPGKTATIACGGENIGRKTVVRQAPGQGLEWMGGIIPSFGTANYAQKFQGRVTITA HWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSDESTSTAYMELSSLRSEDTAVYYCARGPIVATITPL NSGNTATLTISRVEAGDEADYYCQVWDSSSDHDYWGQGTLVTVSS SEQ ID NO. 217 RIFGGGTKLTVL SEQ ID NO. 218 H6B2QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW SYELMQPPSVSVAPGKTATIACGGENIGRKTVVRQAPGQGLEWMGGIIPAFGTANYAQKFQGRVTITA HWYQQKPGQAPVLVIYYDSDRPSGIPERFSGSDESTSTAYMELSSLRSEDTAVYYCARGPIVATITPL NSGNTATLTISRVEAGDEADYYCQVWDSSSDHDYWGQGTLVTVSS SEQ ID NO. 219 RIFGGGTKLTVL SEQ ID NO. 220 H19CQVQLVQSGAEVKKPGASVKVSCKTSGNTFTNYALHW DIVMTQSPPSLSASVGDRVTITCRASQSISSYVRQAPGQGLEWMGGMKPSGGSTSIAQKFQGRVTMTR LNWYQQKPGKAPKLLIYATSSLQYGVPSRFSGDKSTSTVYMELSSLTSEDTAVYYCARDLFPHIFGNY SGSGTDFTLTISSLQPEDFATYYCQGSYSTPYYGMDIWGQGTTVTVSS SEQ ID NO. 221 TFGQGTKVEIK SEQ ID NO. 222 H110DQVQLVQSGAEVKKPGASVKVSCKTSGNTFTNYYMHW DIVMTQSPPSLSASVGDRVTITCRASQSISSYVRQAPGQGLEWMGSMQPSGGSTSLAQKFQGRVTMTR LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGDKSTSTVYMELSSLTSEDTAVYYCARDLFPHILGNY SGSGTDFTLTISSLQPEDFATYYCQGSYSTPYYGMDIWGQGTTVTVSS SEQ ID NO. 223 TFGQGTKVEIK SEQ ID NO. 224 H11FQVQLVQSGAEVKKPGASVKVSCKTSGNTFTNYPMHW DIVMTQSPPSLSASVGDRVTITCRASQSISSYVRQAPGQGLEWMGSMKPSGGSTSLAPKFQGRVTMTR LNWYQQKPGKAPKLLIYAASSLQYGVPSRFSGDKSTSTVYMELSSLTSEDTAVYYCARDLFPHIIGNY SGSGTDFTLTISSLQPEDFATYYCQGSYSTPYYGMDIWGQGTTVTVSS SEQ ID NO. 225 TFGQGTKVEIK SEQ ID NO. 226 H1C1QVQLVQSGAEVKKPGASVKVSCKTSGNTFTNYSMHW DIVMTQSPPSLSASVGDRVTITCRASQSISSYVRQAPGQGLEWMGIMNPSGGSTSYAQKFQGRVTMTR LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGDKSTSTVYMELSSLTSEDTAVYYCARDLFPHIYGNY SGSGTDFTLTISSLQPEDFATYYCQQSYSTPYYGMDIWGQGTTVTVSS SEQ ID NO. 227 TFGQGTKVEIK SEQ ID NO. 228 GPG1A2EVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHW DIVMTQSPSSLSASVGDRVTITCRASQSISSFVRQAPGQGLEWMGWINPNSDNTGSAQKFQGRVFMTK LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGTTSLNTAYMELSGLRSEDTAIYYCARERSSGYFDFW SGSGTDFTLTISSLQPEDFATYYCQQSYSTPIGQGTLVTVSS SEQ ID NO. 229 TFGQGTKVEIK SEQ ID NO. 230 GPGG8QVQLVQSGAEVKKLGASVKVSCKASGYPFTGYYMHW DIVMTQSPSSLSASVGDRVTITCRATPSTSSYVRQAPGQGLEWMGWINPNGDNTGLAQKFQGRVFMTK LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGTTSLNTAYMELSGLRSEDTAIYYCARERSSGYFDFW SGSGTDFTLTISSLQPEDFATYYCQQSYSTPIGQGTLVTVSS SEQ ID NO. 231 TFGQGTKLEIK SEQ ID NO. 232 GPGG10QVQLVQSGAEVKKPGASVKVSCKTSGYPFTGYYMHW DIVMTQSPSSLSASVGDRVTITCRASQSISSYVRQAPGQGLEWMGWINPLSDTTGSAQKFQGRVFMTK LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGTTSLNTAYMELSGLRSEDTAIYYCARERSSGYFDFW SGSGTDFTLTISSLQPEDFATYYCQQSYSTPIGQGTLVTVSS SEQ ID NO. 233 TFGQGTKLEIK SEQ ID NO. 234 GPGH7QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHW DIVMTQSPSSLSASVGDRVTITCRASQSISSFVRQAPGQGLEWMGWINPLSDNTGSAQKFQGRVFMTK LNWYQQKPGKAPKLLIYLASSLQSGVPSRFSGTTSLNTAYMELSGLRSEDTAIYYCARERSSGYFDFW SGSGTDFTLTISSLQPEDFATYYCQQSYSTPIGQGTLVTVSS SEQ ID NO. 235 TFGQGTKVEIK SEQ ID NO. 236 GPGH10QVQLVQSGAEVKKPGASVKVSCKTSGYTFTGYYMHW DIVMTQSPSSLSASVGDRVTITCRASQSISSFVRQAPGQGLEWMGWINPNSDNTGYAQKFQGRVFMTK LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGTTSLNTAYMELSGLRSEDTAIYYCARERSSGYFDFW SGSGTDFTLTISSLQPEDFATYYCQQAYSTPIGQGTLVTVSS SEQ ID NO. 237 TFGQGTKVEIK SEQ ID NO. 238 GPGH11QVQLVQSGAEVKKPGASVKVSCKASGYPFTGYYMHW DIVMTQSPSSLSASVGDRVTITCRASQSISSYVRQAPGQGLEWMGWINPLSDSTGSAQKFQGRVFMTK LNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGTTSLNTAYMELSGLRSEDTAIYYCARERSSGYFDFW SGSGTDFTLTISSLQPEDFATYYCQQSYSTPIGQGTLVTVSS SEQ ID NO. 2 SEQ ID NO. TFGQGTKLEIK SEQ ID NO. 240 239GPGH10P QVQLVQSGAEVKKPGASVKVSCKTSGYTFTGYYMHWDIVMTQSPSSLSASVGDRVTITCRASQSISSF VRQAPGQGLEWMGWINPNSDNTGYAQKFQGRVFMTKLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSG TTSLNTAYMELSGLRSEDTAIYYCARERSSGYFDFWSGSGTDFTLTISSLQPEDFATYYCQQPYSTPI GQGTLVTVSS SEQ ID NO. 241TFGQGTKVEIK SEQ ID NO. 242

We claim:
 1. A recombinant fully human anti-PD-L1 antibody, or anantigen-binding fragment thereof, comprising a heavy chain variabledomain comprising complementarity determining regions (CDRs) as setforth in the heavy chain variable domain amino acid sequence of SEQ IDNO: 221; and comprising a light chain variable domain comprising CDRs asset forth in the light chain variable domain amino acid sequence of SEQID NO:
 222. 2. The anti-PD-L1 antibody of claim 1, wherein the antibodyis an IgG.
 3. The anti-PD-L1 antibody, or antigen binding fragmentthereof, of claim 1, wherein the heavy chain variable domain comprises asequence at least 95% identical to the amino acid sequence of SEQ ID NO:221, and the light chain variable domain comprises a sequence at least95% identical to the amino acid sequence of SEQ ID NO:
 222. 4. Theanti-PD-L1 antibody, or antigen binding fragment thereof, of claim 1,wherein the heavy chain variable domain comprises the amino acidsequence of SEQ ID NO: 221, and the light chain variable domaincomprises the amino acid sequence of SEQ ID NO:
 222. 5. The antigenbinding fragment of the anti-PD-L1 antibody of claim 1, wherein thefragment is a Fab fragment.
 6. The antigen binding fragment of theanti-PD-L1 antibody of claim 1, wherein the fragment is a single chainhuman antibody.
 7. A pharmaceutical composition comprising theanti-PD-L1 antibody, or antigen-binding fragment thereof, of claim 1,and a pharmaceutically acceptable excipient.
 8. A method of treating ahuman subject having cancer comprising administering an effective amountof the anti-PD-L1 antibody, or antigen binding fragment thereof, ofclaim
 1. 9. The method of claim 8, wherein the cancer is selected fromthe group consisting of ovarian cancer, colon cancer, breast cancer,lung cancer, myeloma, a neuroblastic-derived CNS tumor, a monocyticleukemia, a B-cell derived leukemia, a T-cell derived leukemia, a B-cellderived lymphoma, a T-cell derived lymphoma, skin cancer, small celllung cancer, non-small cell lung cancer (NSCLC), head and neck cancer,pancreatic cancer, bladder cancer, bone cancer, cartilage cancer, livercancer, lymph node cancer, nervous tissue cancer, skeletal musclecancer, spinal cord cancer, spleen cancer, brain cancer, colorectalcancer, thyroid cancer, prostate cancer, vaginal cancer, kidney cancer,thymus cancer, thyroid cancer, stomach cancer, cancer of the urogenitaltract, cancer of the ureter, cancer of the urethra, cancer of theuterus, cancer of the testes, and a mast cell derived tumor.
 10. Amethod for treating a human subject having cancer, said methodcomprising administering an effective amount of the fully human antibodyFab fragment of claim 5 to the human subject.
 11. A method for treatinga human subject having cancer, said method comprising administering aneffective amount of the single chain human antibody of claim 6 to thehuman subject.
 12. A nucleic acid encoding an antibody heavy chainvariable domain comprising complementarity determining regions (CDRs) asset forth in the heavy chain variable domain amino acid sequence of SEQID NO: 221, and comprising an antibody light chain variable domaincomprising CDRs as set forth in the light chain variable domain aminoacid sequence of SEQ ID NO:
 222. 13. The nucleic acid of claim 12,wherein the heavy chain variable domain comprises a sequence at least95% identical to the amino acid sequence of SEQ ID NO: 221, and thelight chain variable domain comprises a sequence at least 95% identicalto the amino acid sequence of SEQ ID NO:
 222. 14. The nucleic acid ofclaim 12, wherein the antibody heavy chain comprises a heavy chainvariable region having an amino acid sequence of SEQ ID NO: 221, and theantibody light chain comprises a light chain variable region having anamino acid sequence of SEQ ID NO:
 222. 15. The nucleic acid of claim 12,wherein the antibody is an IgG, a Fab fragment, or a single chain humanantibody.
 16. An expression vector comprising a promoter operably linkedto the nucleic acid of claim
 12. 17. A host cell harboring the nucleicacid of claim 12 or an expression vector comprising a promoter operablylinked to the nucleic acid of claim
 12. 18. A method for expressing arecombinant fully human anti-PD-L1 antibody, or an antigen-bindingfragment thereof, comprising culturing a population of the host cell ofclaim 17 under conditions suitable for expressing the recombinant fullyhuman anti-PD-L1 antibody, or an antigen-binding fragment thereof. 19.The method of claim 18, further comprising recovering from the host cellpopulation the expressed recombinant fully human anti-PD-L1 antibody, oran antigen-binding fragment thereof.